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EsPhALL Amendment : European intergroup study on post-induction treatment of Ph

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ALL
Version 6.0 du 25 mars 2010

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EsPhALL: Amendment proposal
An open-label study to evaluate the safety and efficacy
of IMATINIB with chemotherapy in pediatric patients with Ph+/BCR-ABL+
acute lymphoblastic leukemia (Ph+ALL)






Version 2010





STUDY COMMITTEE

A. Biondi, M. Schrappe Study Chair
M.G. Valsecchi Statistician
M. Aric
G. Mann
G. Janka-Schaub
Y. Benoit
V.Gandemer
A.Castor
V.Saha
R.Pieters
J. Stary
P. De Lorenzo Trial Data Center


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LIST OF PARTICIPATING GROUPS
AIEOP

Prof. Maurizio Aric
Dipartimento Oncoematologia Pediatrica e Cure Domiciliari
Azienda Ospedaliero-Universitaria Meyer
Viale Pieraccini, 24
50139 Firenze, Italy
Tel. +39-055-5662-739
Fax +39-055-5662-746
email:m.arico@meyer.it
ALL-BFM-A


Dr. Georg Mann
St. Annas Childrens Hospital
Kinderspitalgasse 6
1090 Wien, Austria
Tel. + 43 140170250
Fax + 43 14017070
Email:georg.mann@stanna.at
ALL-BFM-G/CH


Prof. Dr. M. Schrappe
Department of Pediatrics
University Medical Center
Schleswig-Holstein, Campus Kiel
Arnold-Heller-Str. 3, Building 9
D-24105 Kiel
Tel: +49 (0) 431-597 1621
Fax: +49 (0) 431-597 3966
Email m.schrappe@pediatrics.uni-kiel.de
COALL


Prof. G. Janka-Schaub
Universittskinderklinik.
Martinstrae 52
20246 Hamburg, Germany
Tel. + 49 40 4717 3796
Fax + 49 40 4717 4601
Email janka@uke.uni-hamburg.de
EORTC


Prof. Y. Benoit
University Hospital
Klinik Voor Kinderziekten C. Hooft
De Pintelaan 185
9000 Gent, Belgium
Tel +32 92403576
Fax + 32 92404986
Email yves.benoit@ugent.be
FRALLE


Dott V. Gandemer
Unite dhemato-oncologie et greffes de moelle
CHU Hopital Sud
16d de Bulgarie
35203 Rennes Cedex 2- France
Tel. +33 299265835
Fax +33 299267195
Email virginie.gandemer@chu-rennes.fr
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NOPHO


Dott. A. Castor
Lund University Hospital
Getingevgen 4
22185 Lund, Sweden
Tel.+ 46 178 264
Fax + 46 130 573
Email:anders.castor@skane.se
MRC


Prof. V. Saha
Cancer Research UK Children's Cancer Group
Paterson Institute of Cancer
University of Manchester
Manchester M20 4BX
Tel (off): +44 161 446 3094
Fax (off): +44 161 446 3092
Tel (lab): +44 161 446 3234
Email v.saha@cancer.org.uk
DCOG Prof Rob Pieters
Erasmus MC-Sophia Childrens Hospital
University Medical Center Rotterdam
Dr. Molewaterplein 60
3015 GJ Rotterdam
The Netherlands
Tel. + 31 10 703 6691
Fax. + 31 10 703 6801
Email rob.pieters@erasmusmc.nl

CPH Prof. Jan Stary
Department of Pediatric Hematology and Oncology
University Hospital Motol
Vuvalu 84
15018 Praha 5-Motol-Czech Republic
Tel.+42 22 443 6401
Fax +42 22 443 6420
Email jan.stary@lfmotol.cuni.cz
PINDA Prof. Dr. Myriam Campbell,
Division of Pediatric Hematology-Oncology
Hospital Roberto del Ro
University of Chile
Santiago, Chile
Tel.+ 56 2 2392765
Fax +565 2 7350725
Email: myriamcampbellb@gmail.com
HONG KONG Dr.Chi-Kong Li
Department of Paediatrics
Prince of Wales Hospital
Shatin, Hong Kong, China
Tel.+ 852 2 632 1019
Fax +852 2 649 7859
Email ckli@cuhk.edu.hk

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COORDINATION UNIT

A.Biondi
G. Lucchini
Centro M.Tettamanti
Clinica Pediatrica Universit Milano-Bicocca
Ospedale S.Gerardo
20052 MONZA
Tel. +39-039-2333661
FAX +39-039-2332167
Email: abiondi.unimib@gmail.com
g.lucchini@hsgerardo.org

M.Schrappe
Department of Pediatrics
University Medical Center
Schleswig-Holstein, Campus Kiel
Arnold-Heller-Str. 3, Building 9
D-24105 Kiel
Tel: +49 (0) 431-597 1621
Fax: +49 (0) 431-597 3966
Email m.schrappe@pediatrics.uni-kiel.de

TRIAL DATA CENTER
M.G.Valsecchi
P. D. Lorenzo
CORS (Operating Center for Research and Statistics)
Clinica Pediatrica Universit Milano-Bicocca
Ospedale S.Gerardo
Via Donizetti,106
20052 MONZA
Tel. +39-039-2333074
Fax +39-039-2332314/ 2167
Email cors@unimib.it
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INDEX

Title Page...1
List of participating Groups. 2
Coordinator Details ..4
Index .5
List of abbrevations...6
Protocol Synopsis. 7-8
1.0 Introduction .....9-18
2.0 Study Population. 19-20
3.0 Study Objectives .....20-21
4.0 Overall Study Design . 22-23
5.0 Treatment Plan . 24-37
5.1 Frontline induction...24
5.2 Phase I B .24-25
5.3 HR1 .25-27
5.4 HR2 .. 28-29
5.5 HR3 .. 30-31
5.6 Reinduction (Protocol II) . 32-33
5.7 Interim Maintenance. 34
5.8 2nd Administration of Prot II... 35-36
5.9 Continuation Therapy .....37
6.0 Investigational drug.38
7.0 Transplant recommendations ...39
8.0 Phase Toxicity Data 39-41
9.0 Visit Schedule and Assessment ..42-45
10.0 Statistical Analysis ..............................................46-51
11.0 Data Management.................................................... 51- 53
12.0 Definitions ..54-55
13.0 References.... 56-59
Appendix I Monitoring of MTX serum levels.. 60
Appendix II Performance Scores...61
Appendix III Drugs....62
Appendix IV Variables in the database......63-69
Appendix V Serious Adverse Event Report.. 70-72



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List of abbreviations

AE adverse event
ALL acute lymphoblastic leukemia
ALT alanine aminotransferase
ANC absolute neutrophil count
AST aspartate aminotransferase
AUC area under the curve
BCR breakpoint cluster region
BSA body surface area
BUN blood urea nitrogen
CML chronic myeloid leukemia
CRF case report/record form
ECG Electrocardiogram
HSCT hematopoietic stem cell transplantation
IRB/EC Institutional Review Board/Ethics Committee
LDH lactic dehydrogenase
Ph
chromosome
Philadelphia chromosome
PK Pharmacokinetic
PLT platelet count
RT-PCR reverse-transcriptase polymerase-chain-reaction
SAE serious adverse event
SGOT serum glutamic-oxaloacetic transaminase
SGPT serum glutamic-pyruvic transaminase
TdT terminal deoxynucleotidyl transferase
ULN upper limit of normal range
WBC white blood cell count

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PROTOCOL SYNOPSIS
Title An open-label study to evaluate the safety and efficacy of
IMATINIB with chemotherapy in pediatric patients with
Ph+/BCR-ABL+ Acute Lymphoblastic Leukemia (Ph+ALL).
Study phase Phase II
Patients and Stratification Pediatric patients with Philadelphia-Positive ALL (Ph+ALL) will
be stratified as Good-Risk Ph+ALL and Poor-Risk Ph+ALL.
a. Poor-Risk group: for protocols which adopt a steroid prephase
patients who are Prednisone-poor responder (i.e. blast cell
count 1000/l in peripheral blood after 7 days of Prednisone
given in combination with intrathecal Methotrexate), for
protocols which do not adopt steroid prephase patients who
have M3 BM at day 15 or M2/M3 BM at day 21; for all
protocols patients who do not achieve CR after the induction
course.
b. Good-Risk group: for protocols which adopt a steroid prephase
patients who are Prednisone-good responder (i.e. blast cell
count < 1000/l in peripheral blood after 7 days of Prednisone
given in combination with intrathecal Methotrexate) and
achieve CR after the induction course;
for protocols which do not adopt steroid prephase patients who
have M1/M2 BM at day 15 or M1 BM at day 21 and
achieve CR after the induction course.
The expected stratification of the Ph+ALL population is as
follows: 25-30% in the Poor-Risk group and 70-75% in the Good-
Risk group.
Primary objective


To evaluate in patients with Ph+ALL the efficacy and safety of
IMATINIB continuous exposure on top of intensive, BFM-type
chemotherapy. The endpoint for response will be the evaluation on
the long-term clinical outcome.
Secondary objectives
A. To compare the outcome with historical controls of patients
treated with BFM oriented protocols (including patients treated
with Imatinib in the original EsPhALL protocol) and with recent
results from the COGAALL0031 (Children Oncology Group-
USA) study, which adopts a more intensive chemotherapy
approach than BFM.
B. To evaluate the overall EFS, DFS and survival in both risk
groups.
C. To assess the antileukemic potential of IMATINIB given to
patients with Ph+ALL. The pattern of the molecular response will
be analyzed on the basis of 5 measurements taken at different time
points from the beginning of phase IB to the beginning of the
reinduction phase or HSCT. The findings will be compared with
historical controls.
D. To evaluate the impact of HSCT on prognosis (EFS/DFS).
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E. To evaluate the impact of MRD on prognosis (EFS/DFS).
F. To evaluate possible delays in chemotherapy administration
under Imatinib continuous exposure
Treatment groups

The target population includes patients aged more than 365 days
and less than 18 years with documented Ph+ALL enrolled in the
national study groups of AIEOP, BFM-G/CH and BFM-A,
COALL, DCOG, EORTC, FRALLE, UKALL, NOPHO,CPH,
PINDA and HONG KONG.
Study design International, intergroup, multicenter, open-label, phase II study
Study size
Overall, these groups are expected to contribute 55 Ph+ALL
patients per year.
Study duration Start of patient enrollment in January 2010. Duration of
enrollement 2 years.
Eligibility Criteria
Inclusion criteria
Children and adolescents aged 1-17 years at diagnosis, with
Ph+ALL documented by either cytogenetics , PCR or FISH for
bcr-abl, who are eligible for the current local prospective
therapeutic study of childhood ALL and for whom informed
consent was given by the parents or by legal guardian.
Eligibility Criteria
Exclusion criteria
On day 15 at the start of
The first course of
IMATINIB



1.Abnormal hepatic function (ALAT/ASAT > 10 times the upper
limit of the normal range);
2.Abnormal renal function ( creatinine > 1.5 times the upper limit
of the normal range or a calculated creatinine clearance of 80ml/
min or less, adjusted to a body surface area of 1.73 sqm);
3.Active systemic bacterial, fungal or viral infection as
documented by positive cultures, radiological imaging techniques,
septic shock symptoms.
Primary endpoint
Long term clinical outcome in Ph+ALL, will be evaluated with
Disease free survival (DFS). DFS will be calculated as the time
from accrual to either one of the following events: relapse, death
in CCR, second malignancies.
Secondary endpoints
1. Feasibility and safety of the addition of IMATINIB to
conventional chemotherapy schedule.
2. Long term clinical outcome ( EFS, survival)
3. Pattern of molecular response at the 5 scheduled time points for
MRD measurement.
4. Conversion rate to CR in patients resistant to the first part of the
induction phase of chemotherapy included in the Poor-risk group.

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1. Introduction
1.1 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL)
Clinical features and results of chemotherapy and stem cell transplantation.
Recent advances in treatment have increased the cure of childhood ALL to 75 percent or better
(1,2). However attempts to improve results for resistant subtypes of ALL, such as Ph+ ALL, have
been largely unsuccessful. Overall Ph+ALL, which accounts only for 3-5% of children with ALL
have a dire prognosis (rates of EFS are 25-30% in children and even less in adults) (3). Some
investigators suggest that Ph+ALL in childhood is heterogeneous with regard to sensitivity to
treatment. Good initial response to steroids (which are given in combination with intrathecal
methotrexate before induction chemotherapy is instituted) as well as age and leukocyte count at
diagnosis, have been shown to correlate with a good clinical outcome in children treated only with
chemotherapy (3,4). The heterogeneity of Ph+ALL with respect to clinical outcome has been
confirmed by the analysis of the largest series of pediatric ALL treated by 10 European and United
States study groups or large single institutions from 1986 to 1996 (3). Among patients who
presented with WBC higher than 100,000 per cubic millimeter, 85% did not have long-term EFS at
five years. The inadequacy of current therapy for such patients, most of whom can be readily
identified by their initial response to prednisone, indicates a need for new treatments. Patients who
are younger than 10 years old and have a WBC less than than 50,000 per cubic millimeter at the
time of diagnosis have about a 50 percent chance of long term DFS whereas the remaining patients
( those with WBC of 50,000 to 100,000 per cubic millimeter and those with less than 50.000
leukocytes per cubic millimeter who are older than 10 years of age) have an intermediate prognosis
( estimate of five-year DFS, 30 %) (3, 5). Stem cell transplantation from HLA-matched related
donor yielded till recent updates a significant better outcome than chemotherapy alone (3,6). The
absence of any significant superiority to chemotherapy in patients undergoing SCT from a
mismatched donor or matched unrelated donor (MUD), could be explained by the high number of
transplantation-related deaths, reported in this study (6). In most recent years better results have
been obtained with unrelated donor HSCT, in series which include either children and adults (7).
The leukemic cell burden present before HSCT influences the rate of relapse-free survival: patients
with detectable BCR-ABL-expression prior to HSCT have a significantly worse prognosis.
Overall these findings underline the need of large prospective cooperative studies worldwide to
generate and test relevant hypothesis to gain better clinical results in a dismal subset of ALL in
children. For these studies it has been evaluated that initial response to therapy identified patients
with different risk (4). This is well documented by the study on the role of response to prednisone in
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the Berlin-Frankfurt-Munster (BFM) protocols (Fig.1)(4) and it has been confirmed, as far as
early morhological bone-marrow evaluation is concerned, by an analysis of the BFM data, as shown
in Fig.2 (M.Shrappe, personal communication ,2002)

0.55, SE=0.08
PRED Good Response (N= 37, 16 events)
0.10, SE=0.07
PRED Poor Response (N= 20, 18 events)
years
Log-Rank p = .0001
P
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
Fig. 1: EFS according to Prednisone Response in Childhood Ph+ ALL
Results from BFM and AIEOP (1986-95)
Schrappe M, Arico M, Harbott J, et al. BLOOD 92 (1998): 2730
12/2001
sti_new.ppt [M.S.]
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Pathogenetic role of the BCR-ABL translocation
Ph+ALL is characterised by a reciprocal translocation between chromosomes 9 and 22
(Philadelphia chromosome) that fuses genetic sequences of the bcr gene on chromosome 22 with c-
abl sequences translocated from chromosome 9. The chimeric bcr-abl gene generates several types
of fusion proteins, of which the p185
BCR-ABL
form is detectable in 85% of patients with Ph+ALL,
whereras the p210
BCR-ABL
chimeric protein typical of CML is observed in approximately 10% of
patients. The BCR-ABL fusion proteins are characterised by a constitutive protein tyrosine kinase
(PTK) activity that is absent in the normal ABL protein. This dysregulated PTK activity, which
results in changes of multiple signal transduction pathways, is crucial to the transforming activity of
the BCR-ABL fusion proteins and their ability to cause leukemias in vivo . Therefore, inhibition of
the PTK activity of this oncoprotein is a rational therapeutic approach for BCR-ABL expressing
leukemia (15).
The ABL tyrosine kinase inhibitor IMATINIB
IMATINIB is an inhibitor of the protein-tyrosine kinases associated with Bcr-Abl, the platelet-
derived growth factor (PDGF) receptor and c-Kit, but not of other members of the Type III receptor
kinase family, such as Flt-3 and Fms (reviewed in Ref. 16). IMATINIB shows selectivity for the
Abl protein-tyrosine kinase at the in vitro, cellular and in vivo level (17). The compound
BM-15: 0 - 4 %: .49, SE=.13 (N= 20, 9 events)
BM-15: 5 - 24 %: .25, SE=.11 (N= 17, 12 events)
BM-15: >=25 %: .00, SE=.00 (N= 17, 16 events)
years
s
tu
k
o
0
7
0
1
.
ta
b

2
1
D
E
C
0
1
P
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8
Log-Rank p: 1-2 = .09
1-3 = .0003; 2-3 = .08
Fig. 2: EFS in childhood Ph+ ALL according to BM response day 15
ALL-BFM patients enrolled 4/90-6/99
12/2001
sti_new. ppt [M.S.]
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specifically inhibits proliferation of Bcr-Abl expressing cells. In colony forming assays using ex
vivo peripheral blood and bone marrow samples, IMATINIB shows selective inhibition of Bcr-Abl
positive colonies from CML patients (18). In animal models, the compound shows potent anti-
tumor activity against Bcr-Abl and v-Abl expressing cells at tolerated doses. Studies in bcr-abl
CML patients showed a hematological response in 95% of patients in the chronic phase, 60% in
accelerated phase and 30% in blast crisis. The cytogenetic response rates in these 3 groups were
respectively 60%, 24% and 16% (19-22).
Inhibition of the Bcr-Abl kinase has been shown to have anti-leukemic effects not only in chronic
myeloid leukemia but also the subset of B-precursor ALL characterised by the translocation (9;22)
which leads to formation of the Philadelphia chromosome. In 2001 IMATINIB has been registered
for CML treatment and it is currently being tested in several phase II and III trials covering most
Ph+ALL patients (ALL0031, EsPhALL).
Results of IMATINIB in Ph
+
ALL
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph
+
ALL) represents a suitable
disease target for therapy with IMATINIB given that the Bcr-Abl kinase is believed to play a
dominant leukemogenic role in this disease. The activity of single-agent imatinib was initially
investigated in patients with relapsed or refractory Ph+ ALL. A phase 1 clinical trial of imatinib at
doses of 300 to 1000 mg daily led to a 70% hematologic response rate with a 20% CR rate (19). A
phase 2 trial of intermediate-dose imatinib yielded a CR rate of 29% (19,23,24). Disease recurrence
was usually observed within a median of 2 months, and responses were durable only in a minority
of patients. Relapse in the central nervous system (CNS) was not uncommon, as imatinib
concentrations in the cerebrospinal fluid only reach 1% to 2% of detectable serum levels,
emphasizing the need for concurrent CNS prophylaxis (25). However, despite its activity in this
disease, treatment of patients with advanced, i.e. relapsed or refractory Ph+ALL with IMATINIB,
has in most cases had only temporary effects, with frequently rapid occurrence of resistance (23,
24). Resistance to IMATINIB is established via an increase in BCR/ABL mRNA, amplification of
the oncogene, altered drug metabolism/transport, point mutations of the ABL catalytic domain (26)
or compensatory mutations in genes other than BCR/ABL.
Imatinib was thus incorporated into combination chemotherapy regimens typically used for de novo
Ph+ ALL, either concurrently (simultaneous imatinib and chemotherapy) or sequentially
(alternating imatinib with chemotherapy). The first report of a clinical trial of this nature included
20 patients with de novo or minimally treated Ph+ ALL (no age restrictions) (27). Imatinib was
given concurrently with the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine,
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doxorubicin, and dexamethasone alternating with cycles of high-dose methotrexate and cytarabine);
CR rate was 96%, with a 2-year DFS rate of 85%. The molecular remission rate or negativity for
BCR-ABL transcripts by RT-PCR and nested PCR approached 60%. The addition of imatinib to the
chemotherapy improved outcome. Lee et al also reported favorable outcomes after incorporating
imatinib into a conventional L-asparaginasebased ALL regimen for newly diagnosed Ph+ ALL
(28).
Yanada et al observed a CR rate of 96% and molecular remission rate of 71% in de novo patients
with Ph+ ALL aged less than 65 years after concurrent imatinib and induction chemotherapy
followed by alternating blocks of imatinib and consolidation chemotherapy (29). Long-term DFS
and overall survival rates were significantly superior to the historical experience in these studies. In
a subsequent report of outcome with imatinib-based frontline chemotherapy, two sequential cohorts
of patients with de novo Ph+ ALL were treated according to German Multi-Centre Acute
Lymphoblastic Leukemia (GMALL) protocols. First, a treatment regimen consisting of alternating
blocks of chemotherapy and single-agent imatinib was designed because of concerns of potential
toxicity. Once the feasibility and tolerance of concurrent imatinib and chemotherapy was
demonstrated by other investigators, a concurrent regimen was implemented. The superiority of the
latter approach was evidenced by a higher rate of molecular remission (52% vs 19%; P >.01),
although the greater antileukemia efficacy did not translate into significant improvements in DFS or
overall survival compared with the alternating regimen (30).
Tolerability of IMATINIB
In over 3000 patients treated, IMATINIB has been generally well tolerated, enabling chronic once
daily oral dosing. There has been one death due to hepatic toxicity in a 58-year-old Indian patient in
CML accelerated phase treated at the 600 mg/daily in which the causality assessment to trial drug
was suspected. As this patient was taking acetaminophen 0.5 gm 6-8 times/daily, a drug interaction
between IMATINIB and acetaminophen has to be considered. This death occurred against a
background of Grade 2/3 elevations in liver transaminases in seven patients, without a clear dose-
relationship. These elevations were often attributed to progression of the underlying disease. When
suspected to be related to study drug, they were managed successfully by temporary discontinuation
of drug, whereupon transaminase values promptly decreased. Modest dose reductions upon re-
initiation of therapy were performed for Grade 3 toxicity, and no patient has permanently
discontinued therapy due to hepatic toxicity.
The most commonly reported adverse event related to imatinib administration was mild nausea,
which has been observed in more than 40% of patients. It is now established that nausea may be
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prevented or mitigated by the prior ingestion of a small snack. Arthralgias, myalgias and periorbital
edema have each been observed in 10% of patients. Interstitial edema and weight gain have been
seen in some patients treated with 600 mg and 750 mg/daily; however, these findings were not
associated with capillary leak syndrome and no patient has experienced congestive heart failure or
other adverse events as a result of fluid retention.
Several patients have experienced episodes of gastrointestinal bleeding associated with erosions at
the gastroesophageal junction and presumed due to the irritant effect of the drug.
In a phase II study published by Ottmann in 2002 (24), Imatinib toxicity profile was similar to that
observed in the trials of single agent imatinib for Ph+ CML, and included transient
myelosuppression, fluid retention syndrome, nausea, muscle cramps, rash, and transient elevations
in hepatic transaminases. When incorporated into combination chemotherapy regimens the safety
profile of the drug still proved to be tolerable. Not surprisingly, the use of concurrent imatinib and
L-asparaginase often resulted in hyperbilirubinemia, requiring dose interruptions or modifications
of therapy.
Experience of IMATINIB in pediatric patients
A Phase I study of Imatinib, POG-P9973, was conducted by POG to estimate the maximum
tolerated dose (MTD) of Imatinib administered orally once daily, without interruption to children
with recurrent Ph+ leukemia.
No MTD was observed up to 570 mg/m
2
,equivalent to the adult phase 2 and 3 dose. Grade 3-4
neutropenia was seen in the 23 of 93 courses, thrombocytopenia in 16 of 93 courses. Some of the
hematologic toxicity may have been secondary to underlying leukemia as they were present in 25-
30% during the first course of treatment. Gr 3-4 diarrhea was observed in 15/ 93, nausea in 16/93
vomiting in 13/93, abdominal cramping 6/ 93. Grade 3 liver enzyme elevation occurred in 1/93.
One intracranial hemorrhage occurred in a patient who was thrombocytopenic and was receiving
enoxaparin.
The most common toxicity was grade 1 nausea, seen in 7 of 14 patients (50%). Diarrhea, vomiting,
abdominal pain and headaches were each reported in 3 patients (21%). Other toxicities reported in 2
patients each included fatigue, stomatitis, bone pain, and various metabolic alterations (increased
alkaline phosphatase, increased AST, hyperglycemia). Patients accrued on the first 3 treatment
levels cumulate a total of 43 courses of treatment (median 3; range 2-8).
The recently completed COG AALL0031 trial established the safety and tested the efficacy of an
intensive chemotherapy backbone plus imatinib in treating children with Ph+ ALL. To date,
addition of imatinib has been safe and associated with relatively minor additional toxicity (mild
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asymptomatic transaminitis requiring intermittent rather than continuous dosing during
Maintenance therapy).
Among pediatric patients with Ph+ ALL, there have been limited reports evaluating the impact of
imatinib on either induction CR rates and/or overall outcomes. In a short report by Fuster et al.
(31), the authors describe four pediatric patients with Ph+ ALL (ages 28 years) treated with
imatinib in combination with chemotherapy prior to proceeding to allogeneic HCT. All patients
achieved a molecular remission (undetectable bcr/abl transcript by RT-PCR) by 16 weeks (range,
216 weeks) from the start of combination therapy and were alive in hematologic remission after a
median time of 24 months (range, 1153 months) from initiating imatinib.
Burke et al reported 37 children diagnosed with Ph+ B-precursor ALL receiving a myeloablative
allogeneic HCT (32). Patients received similar pre-HCT chemotherapy with the majority receiving
BerlinFrankfurtMunster (BFM) based regimens according to Childrens Cancer Group (CCG) or
COG protocols. Thirteen patients received imatinib therapy either pre- and/or post-HCT comprising
the imatinib group. The remaining 24 patients either never received imatinib or received it only at
time of relapse post-HCT. IMATINIB doses ranged from 240 to 340 mg/m
2
/day. Patients treated
with IMATINIB pre-HCT received therapy for a median of 3 months (range, 127 months). When
IMATINIB therapy was used postallogeneic HCT, it was started, on average, on day 120 (range,
80180) and continued for a median of 8 (range, 210) months. OS and DFS at 3 years was 59%
and 62% for the IMATINIB group compared to 58% and 53% for the non-IMATINIB group (P =
0.80 and 0.9 respectively)
Main Study COG AALL0031 (33).
This study was a phase III open, non-controlled, dose-escalation study conducted by the Childrens
Oncology Group (COG), a NCI supported clinical co-operative group, in the US. Study Participants
were male and female patients younger than 21 years old with Very High Risk leukemias including
93 patients with Ph+ leukaemia.
The chemotherapy regimen was based on previous strategies in which patients first received 4
weeks of standard induction chemotherapy and were entered onto AALL0031, which included an
intensive consolidation phase followed by a continuation regimen. All patients received a minimum
of two consolidation chemotherapy blocks. Patients with an HLA-matched related donor entered the
BMT arm following these blocks. Total duration of chemotherapy for those not receiving BMT was
approximately 27 months. For patients with Ph+ALL, imatinib 340 mg/m
2
/d was introduced into
the chemotherapy regimen in a stepwise fashion, with toxicity assessed for each cohort before
progression to the next cohort. Each cohort had 12 subjects except for cohort 1 (n=7), which was
discontinued early on the basis of published data demonstrating acceptable imatinib toxicity with
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high-dose methotrexate. Cohort 5 was expanded to accrue a total of 50 patients to provide a more
precise estimate of outcome. The total imatinib exposure (before maintenance) was 42 days in
cohort 1, 63 days in cohort 2 (n=17), 84 days in cohort 3, 126 days in cohort 4 (n=22), and 280 days
in cohort 5 (n=44). All groups received an additional 336 days of imatinib exposure in maintenance
cycles 1 through 12. For all patients receiving BMT on protocol, imatinib was started between week
16 and week 24 after BMT when the absolute neutrophil count was 750 and the platelet count was
75,000 given for a total of 24 weeks. Dosing started at 230mg/m
2
/d and increased after 28 days to
340 mg/m
2
/d if no grade 3 or 4 toxicity was observed.
This study aimed to determine the the feasibility in terms of patient accrual and toxicity of an
intensified chemotherapeutic regimen incorporating novel agents for treatment of children and
adolescents with very high risk ALL.
The 3-year EFS of patients in cohort 5 receiving continuous imatinib was 80.5%11.2% (95% CI,
64.5% to 89.8%), including those assigned to a sibling BMT. This is significantly higher than
historical controls, after excluding induction failures from previous POG studies (N=120; 3-year
EFS, 35.0%4.4%; P< .0001).
Twenty-one patients had matched sibling transplants (8 of 39 in cohorts 1-4 and 13 of 44 in cohort
5). There was no significant difference in 3-year EFS between patients (n = 25) treated with cohort
5 chemotherapy (87.7%10.9%; 95% CI, 66.4% to 95.8%), patients (n=21) receiving BMT from a
sibling donor (56.6% 21.5%; 95% CI, 30.4% to 76.1%), and patients (n = 11) receiving BMT from
an alternative donor (71.6% 19.0%; 95% CI, 35.0% to 89.9%; P = .14).

Role of Hematopoietic Stem Cell Transplantation (HSCT) in Ph positive ALL
Because of the universally dismal prognosis of de novo Ph+ ALL in the pre-imatinib era, all
patients who achieved CR were recommended to undergo allogeneic SCT as feasible,inclusive of
all stem cell sources such as matched unrelated marrow and umbilical cord blood. The benefits of
SCT in first CR were attributed to the intense myeloablative therapy and graft-versus-leukemia
effect; the high risk of transplantation-related mortality was accepted given the alternative of poor
outcomes with chemotherapy alone. Two large multicenter trials confirmed the benefit of allogeneic
SCT in the pre-imatinib era. In the Ph+ subset of patients with ALL (n=167) enrolled in the
UKALL XII/ECOG E2993 trial, the 5-year relapse risk was decreased from 81% with either
chemotherapy alone or autologous SCT to 32% with allogeneic SCT (8). Five-year event-free
survival (EFS) and overall survival rates improved from 17% to 36% and 19% to 42%, respectively.
Furthermore, the prospective multicenter French, Belgian, Swiss and Australian LALA-94 trial of
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154 patients with Ph+ ALL showed that achievement of negativity for BCR-ABL by RT-PCR and
undergoing allogeneic SCT predicted for improved DFS and overall survival (9).
The role of allogeneic SCT for de novo Ph+ ALL in the imatinib era continues to be refined, with
feasibility of this approach still limited by the availability of an appropriate donor, absence of
significant comorbidities, and ability to sustain a complete remission. Advances in SCT such as the
application of nonmyeloablative reduced intensity conditioning regimens to patients with
comorbidities prohibiting traditional myeloablative regimens, in addition to increased availability of
umbilical cord blood as a source of stem cells, have allowed this modality to be applied in a more
systematic fashion (10).
Several studies have reported an improvement in the rate of allogeneic SCT in first CR after
imatinib-based therapy compared with the prior experience (27,29,30,38). This success is in part
related to (1) an increase in the proportion of sustained remissions, offering additional time for
identification of a suitable donor, and to (2) an improvement in the quality of the remissions (e.g.,
lower levels of BCR-ABL transcripts after imatinib-based therapy), resulting in a lower
pretransplantation tumor burden. Two of the early nonrandomized studies of imatinib-based
chemotherapy for de novo Ph+ ALL applied allogeneic SCT in first CR as standard of care when
feasible. Similar survival outcomes were observed with or without allogeneic SCT, despite the
selection biases favoring SCT (27,29,38). Additional experience and longer follow-up is needed to
clarify whether allogeneic SCT can be deferred in a select group of patients with Ph+ ALL
otherwise eligible for this modality. To this regard, the Gandemer series identified two groups of
patients with marked differences in five-year outcome: children with age<10, leukocyte count
<100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event
free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55%
CR, EFS: 18%, OS: 27%) (p < 0.005) (41). The combination of available tools such as minimal
residual disease assessment with determination of these simple factors could be useful for refining
indications for BMT in the current era of tyrosine-kinase inhibitor-based treatment.
Postallogeneic SCT maintenance strategies are also being explored, particularly as the detection of
minimal residual disease (MRD) following SCT predicts imminent relapse in the absence of
intervention (40). Wassmann et al (11) investigated the use of single-agent imatinib in the post
transplantation setting after detection of MRD by quantitative RT-PCR for BCR-ABL. Standard-
dose (400 mg) imatinib resulted in eradication of molecular disease in 52% of the 27 patients
treated. Notably, failure to achieve molecular remission within the first 6 weeks of therapy heralded
overt leukemia relapse despite other additional manipulations (e.g., donor lymphocyte infusions).
Using imatinib in the post-transplantation setting in a prophylactic manner, immediately after
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engraftment and prior to the detection of MRD, may further improve outcome by preventing
resurgence of the leukemia clone. Two small series have shown that this approach is feasible, with
transient elevations in hepatic transaminases usually responding to dose interruptions or
modifications (12, 13). Additional experience will be required to determine whether imatinib
monotherapy after transplantation would eventually lead to development of resistance.


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2. Study population
2.1 Patient population
The target population includes children and adolescents with newly diagnosed and documented
Ph+ALL enrolled in the treatment front-line protocols of the national study groups of AIEOP,
BFM-G/CH and BFM-A, COALL, DCOG, EORTC, FRALLE, UKALL, NOPHO,CZECH
REPUBLIC, PINDA and HONG KONG.
2.2 Inclusion and exclusion criteria
2.2.1 Inclusion criteria
The criteria for the patients with newly diagnosed Ph+ALL to enter the study are:
1. Age greater than 1 year (365 days) and less than 18 years (17 years and 365 days) at diagnosis.
2. Documented presence of t(9;22)(q34;q11) determined by institutional cytogenetics or FISH
and/or of the presence of BCR-ABL fusion transcript identified by RT-PCR or FISH.
3. Eligibility for the current local prospective therapeutic study of childhood ALL.
4. Informed consent given by the parents or by the legal guardian.
It is important that all children with Ph+ALL, including those who are eligible but are not treated
according to the present protocol will be registered so that any selection bias can be monitored.
2.2.2 Exclusion criteria (on day 15 at the time to start IMATINIB)
1. Abnormal hepatic function (ALAT/ASAT > 10 times the upper limit of the normal range);
2. Abnormal renal function ( creatinine > 1.5 times the upper limit of the normal range or a
calculated creatinine clearance of 80 ml/ min or less, adjusted to a body surface area of 1.73
m
2
);
3. Active systemic bacterial, fungal or viral infection as documented by positive cultures,
radiological imaging techniques, septic shock symptoms.

2.3 Stratification
All patients will receive the induction phase according to national/group study treatment protocol.
Either early response to treatment parameters (PB blast/count after 7 days of prednisone given in
combination with intrathecal methotrexate before induction chemotherapy is instituted; or
evaluation of BM at day 15 and 21) or no achievement of CR (cytology) at the end of induction,
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will allow the definition of Ph+ALL risk- subgroups in the different study groups. More precisely,
the following definitions hold:
c. Poor-Risk group: for protocols which adopt a steroid prephase patients who are Prednisone-poor
responder (i.e. blast cell count 1000/l in peripheral blood after 7 days of Prednisone given in
combination with intrathecal Methotrexate), for protocols which do not adopt steroid prephase
patients who have M3 BM at day 15 or M2/M3 BM at day 21; for all protocols patients who do
not achieve CR after the induction course.
d. Good-Risk group: for protocols which adopt a steroid prephase patients who are Prednisone-
good responder (i.e. blast cell count < 1000/l in peripheral blood after 7 days of Prednisone
given in combination with intrathecal Methotrexate) and achieve CR after the induction course;
for protocols which do not adopt steroid prephase patients who have M1/M2 BM at day 15 or
M1 BM at day 21 and achieve CR after the induction course.

3. Study objectives
3.1 Primary objective
To evaluate in patients with Ph+ALL the efficacy and safety of IMATINIB continuous exposure on
top of intensive, BFM-type chemotherapy. The endpoint will be the evaluation on the long-term
clinical outcome.
3.2 Secondary objectives
To compare the outcome with historical controls of patients treated with BFM oriented
protocols (including patients treated with Imatinib in the original EsPhALL protocol) and with
recent results from the COGAALL0031 (Children Oncology Group-USA) study, which adopts a
more intensive chemotherapy approach than BFM.
To evaluate the overall EFS,DFS and survival.
To assess the antileukemic potential of IMATINIB by analyzing the pattern of molecular
response on the basis of 5 MRD measurements taken at different time points from the beginning
of phase IB to the beginning of protocol II or HSCT at week 22.
To evaluate the impact of MRD on prognosis (EFS/DFS).
To evaluate the impact of HSCT on prognosis (EFS/DFS).
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To evaluate possible delays in chemotherapy administration under Imatinib continuous
exposure

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Fig. 3 European intergroup study on treatment of Ph+ALL with
IMATINIB





4. Overall study design
In the context of Ph+ALL most of the data produced so far have shown only a transient effect in
blast cell reduction. These observation prompted several investigators to consider the use of
IMATINIB in the context of multi-agent approach. The clinical heterogeneity of Ph+ALL will offer
the opportunity to test the impact of IMATINIB in two subgroups of patients as defined by early
response to treatment (Poor and Good Risk Ph+ALL).
While we allow for differences in induction therapies applied by different groups, it is very
important that all subsequent therapy plan is uniform. For this purpose, the current AIEOP-BFM-
ALL 2000 strategy for High-risk patients has been considered appropriate. Treatment starts with
approximately 4 weeks of induction therapy according to the national protocol. During this, the
Ph+ status of the patient has to be determined. After this first induction therapy, further treatment
will be according to the international schedule. This will include a phase IB of induction, followed
by three blocks of treatment as shown in detailed in Fig.4 - 7. With respect to the different
proposed arms for reinduction therapy, the AIEOP variant which included a modified- BFM
protocol II repeated twice, will be used, as shown in Fig.8 , 9.
0 2 10 12
BM sampling
MRD
Timepoints
1 2
22
1b
35
1a
G-
104
IMATINIB 300 mg/m
2
/d
3 4 5
II
cranial RT
II
I
B
H
R
1'
H
R
2'
SCT
H
R
3'
Induction
6
29 42
52
(7) (8)
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Good-risk and Poor Risk Ph+ALL patients will receive IMATINIB starting on day 15 during
Induction phase and continuously troughout the consolidation and reinduction phase of
chemotherapy
All patients will be screened for an HLA-identical family or unrelated donor.

Good-risk patients: patients with a genotype-matched donor (9/10 or 10/10), will receive HSCT,
while the others will continue on chemotherapy, thus receiving IMATINIB in combination with the
standard chemotherapy.

Poor-risk patients: patients will be eligible for any type of donor (matched or mismatched family
donors, unrelated or haploidentical donors). Patients not transplanted will continue on
chemotherapy, thus receiving IMATINIB in combination with the standard chemotherapy.


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5. Treatment plan
5.1 Frontline induction
All patients will receive the first induction according to national/group study treatment protocol.
Imatinib 300 mg/m
2
daily will be introduced on day + 15 from diagnosis

in all patients on top of
ongoing chemotherapy till day + 33.
5.2 Phase IB
Figure 4.




IMATINIB : 300 mg/m
2
/day orally days 1-28 (total 28 days).
All Good and Poor Risk Patients will receive IMATINIB. To allow close patient monitoring, patient
will attend outpatient clinics at least weekly because of ARA-C injections.

Requirements for beginning of phase IB:
1.Good general condition without serious infections;
2.Creatinine level within normal limits according to age;
3.WBC> 2000/l, ANC >500/l; platelets >50,000/l

CYCLOPHOSPHAMIDE (CPM): 1000 mg/m
2
/dose i.v. (1 hour) days 1,28.
BM/MRD

Day
1 8 15
CPM p.i. (1h) 1000 mg/m
2

ARA-C i.v. 75 mg/m
2
/d
22 29
MTX IT
IMATINIB p.o. (28 d) 300 mg/m
2
/d
6-MP p.o. (28 d) 60 mg/m
2
/d

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Associate: * hyperhydratation 3.000 ml/m
2
over 24 hours : G 5%+
NaCl 0,45%+ 90 mEq/m
2
KCl
* MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start).
* FUROSEMIDE 0.5-1 mg/kg i.v if input > output +400ml/ m
2
/12 h.
Please consider adequate anti-emetic supportive therapy.
6-MERCAPTOPURINE (6-MP): 60 mg/m
2
/day p.o., to be taken in the evening on an empty
stomach (1 hour before or after dinner), not together with milk, days 1-28(total 28 days).
CYTOSINE ARABINOSIDE (ARA-C): 75 mg/
2
/day s.c. o i.v. in one daily dose, days 3-6, 10-13,
17-20,24-27.
Each 4-day cycle should be started when WBC >500l and platelets >30.000/l; each cycle when
started should not be stopped unless for acute infection (please consider that fever might be also
induced by the drug).
INTRATECHAL METHOTREXATE : days 3, 17 (together with ARA-C cycles 1 and 3), age-
dosed:
AGE MTX
1 year <2 years 8 mg
2 years <3 years 10 mg
3 years 12 mg

5.3 Consolidation Block 1 (HR1)
Figure 5.


DEXA p.o./i.v. 20 mg/m
2
/d
VCR i.v. (max. 2 mg) 1.5
mg/m
2

HD-ARA-C p.i. (3 h) 2 g/m
2

x2
HD-MTX p.i. (24 h) 5 g/m
2
(10% in 0.5 h, 90% in 23.5 h)
L-ASP p.i. (2 h) 25,000 IU/m
2
(E.coli- MEDAC/KYOWA)

CF-rescue i.v. (h 42, 48, 54) 15
CPM p.i. (1 h) 200 mg/m
2
with MESNA: 70 mg/m
2
h 0, 4, und 8 after CPM

Day 1 2 3 4 5 6 7 20
B
M
/
M
R
D


IMATINIB 300 mg/m
2
/d (d 1-21)
MTX/ARA-C/PRED i.t.
Dose age adapted
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Consolidation therapy will start on day 78 of therapy, provided the patient is in good general
condition and adequate ANC ( 500/l) and platelet counts ( 50.000/l) are documented (rising
counts). Imatinib administration will not be interrupted between the end of phase IB and the
beginning of the first HR block. The interval between each block element should be 21 days (
counting from day 1 of HR-1 to day 1 of HR-2).

DEXAMETHASONE (DXM): 20 mg/m
2
/day p.o. or i.v. in 3 doses, days 1-5 (no tapering).

VINCRISTINE (VCR): 1.5 mg/m
2
/day i.v.(max dose: 2mg), day 1 and 6.
HIGH-DOSE METHOTREXATE (HD-MTX): 5 g/m
2
/dose i.v. over 24 hours on day 1 (1/10 in
30 minutes, the remaining 9/10 in 23.5 hour-infusion ). Hyperhydration: 3.000 ml/m
2
over 24 hours
: Gluc. 5%+ NaCl 0,45%+ 90 mEq/m
2
KCl+NaHCO3 90 mEq/m
2
. Urine pH>7.0 over the time of
infusion.
Serum levels of MTX must be determined at hours 24, 42, 48 from start of MTX infusion. For
monitoring of MTX serum levels and intensification of LCV rescue, see Appendix I.

CITROVORUM FACTOR (Folinic acid): 7.5 mg/m
2
i.v (Levo form) or 15 mg/m
2
i.v (Racemic
form) at hours 42, 48, 54 from start of infusion. For monitoring of MTX serum levels and
intensification of LCV rescue, see Appendix I.
Starting from hour 60, Citrovorum Factor is needed only if serum levels at hour 48 exceed 0.5
mol/l. In this case, see nomogram for therapeutic adjustments.

HIGH-DOSE ARA-C (HD-ARA-C): 2 gr/m
2
/iv in 3-hour infusion, repeated after 12 hours, day 5.
The use of prednisolone eye drops is suggested.

HIGH-DOSE L-ASPARAGINASE (HD-L-ASP): E. coli (medac or kidrolase): 25.000
IU/m
2
/dose, over 2 h i.v., 3 hours after completion of the infusion of the second dose of HD-ARA-
C. In case of an allergic reaction , PEG-ASP(ONCASPAR) may be used in a single dose of 1000
I.E./m
2
over 1 h i.v.

CYCLOPHOSPHAMIDE (CPM): 200 mg/m
2
i.v. in 1 hour q 12 hours, 5 doses, days 2-4. Start
immediately after the completion of HD-MTX infusion. MESNA 70 mg/m
2
hours 0, 4 and 8 from
start of CPM.
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INTRATHECAL THERAPY: day 1, 2 hours after start of HD-MTX, dose according to age:
AGE MTX ARA-C PRED
1 year <2 years 8 mg 20 mg 6 mg
2 years <3 years 10 mg 26 mg 8 mg
3 years 12 mg 30 mg 10 mg

G-CSF: 5 g/kg/day s.c. starting from the 5th day after completion of the block, until the WBC
count is >20.000l

IMATINIB : 300 mg/m
2
/day orally starting from the first day of chemotherapy block and given for
a total of 21 days. IMATINIB should not be given longer than 21 days if next chemotherapy block
has to be postponed.

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5.4 Consolidation Block 2 (HR2)
Figure 6.





DEXAMETHASONE (DXM): 20 mg/m
2
/day p.o. o i.v. in 3 doses, days 1-5 (no tapering).

VINDESINE (VDS): 3 mg/m
2
/day i.v.(max 5 mg), days 1 and 6.
HIGH-DOSE METHOTREXATE (HD-MTX): 5 g/m
2
/dose i.v. on day 1 over 24 hours (1/10 in
30 minutes, the remaining 9/10 over a 23.5 hour-infusion). Hyperhydration: 3.000 ml/m
2
over 24
hours : Gluc. 5%+ NaCl 0,45%+ 90 mEq/m
2
KCl+NaHCO3 90 mEq/m
2
. Urine pH>7.0 over the time
of infusion.
Serum levels of MTX must be determined at hours 24, 42, 48 from infusion start. For monitoring of
MTX serum levels and intensification of LCV rescue, see Appendix I.

CITROVORUM FACTOR (Folinic acid): 7.5 mg/m
2
i.v (Levo form) or 15 mg/m
2
i.v (Racemic
form) at hours 42, 48, 54 from start of infusion. For monitoring of MTX serum levels and
intensification of LCV rescue, see Appendix I.
Starting from hour 60, CF is needed only if serum levels at hour 48 exceed 0.5 mol/l. In this case,
see nomogram for therapeutic adjustments.
VDS i.v. (max. 5 mg) 3.0 mg/m
2

DNR p.i. (24 h) 30 mg/m
2

HD-MTX p.i. (24 h) 5 g/m
2
(10% in 0.5 h, 90% in 23.5 h
L-ASP p.i. (2 h) 25,000 IU/m
2
(E.coli- MEDAC/KYOWA)

CF-rescue i.v. (h 42, 48, 54) 15
IFO p.i. (1 h) 800 mg/m
2
with MESNA: 70 mg/m
2
h 0, 4, und 8 after IFO
Day 1 2 3 4 5 6 7 20
B
M
/
M
R
D

MTX/ARA-C/PRED i.th.
Dose age adapted

IMATINIB 300 mg/m
2
/d (d 1-21)
( )
#
#
only if initially CNS positive
DEXA p.o./i.v. 20 mg/m
2
/d
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IFOSPHAMIDE (IFO): 800 mg/m
2
i.v. over 1-hour infusion, q 12 hours, 5 doses, days 2-4. Start
immediately after completion of HD-MTX infusion. MESNA 300 mg/m
2
i.v hour 0, 4 and 8 from
start of infusion.

HIGH-DOSE L-ASPARAGINASE (HD-L-ASP): E. coli (medac or kidrolase): 25.000
IU/m
2
/dose, over 2 h i.v. In case of an allergic reaction , PEG-ASP(ONCASPAR) may be used in a
single dose of 1000 I.E./m
2
over 1 h i.v., on day 5

DAUNORUBICIN (DNR): 30 mg/m
2
m over 24-hour infusion on day 5

INTRATHECAL THERAPY: day 1, 2 hours after start of HD-MTX, according to age:
AGE MTX ARA-C PRED
1 year <2 years 8 mg 20 mg 6 mg
2 years <3 years 10 mg 26 mg 8 mg
3 years 12 mg 30 mg 10 mg


G-CSF: 5 g/kg/day s.c. starting from the 5
th
day after completion of the block, until the WBC
count is >20x10
9
/l.

IMATINIB : 300 mg/m
2
/day orally starting from the first day of chemotherapy block and given for
a total of 21 days. IMATINIB should not be given longer than 21 days if next chemotherapy block
has to be postponed.
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5.5 Consolidation Block 3 (HR 3)

Figure 7.


DEXAMETHASONE (DXM): 20 mg/m
2
m/day p.o. o i.v. in 3 doses, days 1-5 (no tapering).

HIGH-DOSE ARA-C (HD-ARA-C): 2 g/m
2
i.v. in 3-hour infusion, q 12 hours, 4 total doses, days
1-2.

VP-16: 100 mg/m
2
m i.v. in 1 hour , q 12 hours, 5 total doses, days 3-5.

HIGH-DOSE L-ASPARAGINASE (HD-L-ASP): E. coli (medac or kidrolase): 25.000
IU/m
2
/dose, over 2 h i.v. In case of an allergic reaction ,PEG-ASP(ONCASPAR) may be used in a
single dose of 1000 I.E./m
2
over 1 h i.v. on day 5

INTRATHECAL THERAPY: day 5, dose according to age:
AGE MTX ARA-C PRED
1 year <2 years 8 mg 20 mg 6 mg
2 years <3 years 10 mg 26 mg 8 mg
3 years 12 mg 30 mg 10 mg

G-CSF: 5 g/kg/day s.c. starting from the 5
th
day after completion of the block, until the WBC
count is >20x10
9
/l.
DEXA p.o./i.v. 20 mg/m
2
/d
MTX/ARA-C/PRED i.th.
Dose age adapted

IMATINIB 300 mg/m
2
/d (d 1-20)
VP-16 p.i. (1 h) 100 mg/m
2
x 5
ASP p.i. (2 h) 25,000 E/m
2

(E.coli- MEDAC/KYOWA)
HD-ARA-C p.i. (3 h) 2g/m
2
x 4
B
M
/
M
R
D

Day 1 2 3 4 5 6 7 20
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IMATINIB : 300 mg/m
2
/day orally starting from the first day of chemotherapy block and given for
a total of 20 days. IMATINIB should not be given longer than 20 days if next chemotherapy block
has to be postponed.
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5.6 Reinduction (Protocol II)
Reinduction with protocol II starts 14 days after completion of consolidation block-therapy
(intended as day 5 of HR block 3) provided the patient is in good general condition and adequate
ANC ( 500/l) and platelet counts ( 50.000/l) are documented. Protocol II comprises two
phases, IIa and IIb.

Figure 8.


5.6.1 Phase IIa

DEXAMETHASONE (DXM) : 10mg/m
2
/day p.o. in 3 doses, day 1-21, then tapered over 9 days
by reducing the dose by 50% q 3 days.

VINCRISTINE (VCR): 1.5 mg/m
2
/dose i.v. (maximum dose 2.0 mg/dose), day 8, 15, 22, 29.

DOXORUBICIN (DOX)/ADRIAMYCIN (ADR): 25 mg/m
2
/dose i.v. to be infused over 1h on
days 8, 15, 22, 29.

BM/MRD

Da 1 8 15 2 29 36 4 50
DEXA p.o./i.v. 10 mg/m
2
/d
VCR i.v. 1.5 mg/m
2
CPM p.i. (1 h) 1000 mg/m
2

DOX p.i. (1 h) 25 mg/m
2

L-ASP
(E.coli)
p.i. (1 h) 10,000 U/m
2

ARA-C i.v. 75 mg/m
2
/d
( ( )
#
)
#
57 63
MTX i.th. Dose age adapted
IMATINIB p.o. 300 mg/m
2
/d (d 1-63)
6-TG p.o. (14 d) 60 mg/m
2
/d
#
only if initially CNS positive
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L-ASPARAGINASE (L-ASP) E. coli (medac or kidrolase): 10.000 IU/m
2
/dose, over 1 h i.v.,days
8,11,15 and 18. In case of an allergic reaction , PEG-ASP(ONCASPAR) may be used in a single
dose of 1000 I.E./m
2
over 1 h i.v.

IMATINIB : 300 mg/m
2
/day orally, days 1-35 (total 35 days)

5.6.2 Phase IIb

It starts on day 36 of protocol II provided the patient is in good general condition and adequate
ANC ( 500/l) and platelet counts ( 50.000/l) are documented.

CYCLOPHOSPHAMIDE (CPM): 1000 mg/m
2
/dose i.v. (1 hour) day 36.
Associate: * hyperhydration 3.000 ml/m
2
over 24 hours : Gluc. 5%+ NaCl 0.45%+ 90 mEq/m
2

KCl .
* MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start).
* FUROSEMIDE 0.5-1 mg/kg i.v if input>output +400 ml/m
2
/12h.
Please consider adequate anti-emetic supportive therapy.

6-THIOGUANINE (6-TG): 60 mg/m
2
/day p.o., taken in the evening on the empty stomach without
milk (1 hour before or after dinner), days 36-49 (total 14 days).

CYTOSINE ARABINOSIDE (ARA-C): 75 mg/m
2
/day s.c. o i.v. in one daily dose, days 38-41,
45-48.
Each 4-day cycle should be started when ANC >200/l and platelets >50.000/l; each cycle when
started should not be stopped unless for acute infection (please consider that fever might be also
induced by the drug).
INTRATHECAL METHOTREXATE : days 38, 45 (together with ARA-C cycles),dosage
according to age:
AGE MTX
1 year <2 years 8 mg
2 years <3 years 10 mg
3 years 12 mg

IMATINIB : 300 mg/m
2
/day orally, days 36-63 (total 28 days) for all patients

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5.7 Interim maintenance

This short phase is aimed to allow administration of cranial irradiation during antimetabolite-based
non-intensive chemotherapy. It will start 2 weeks after completion of the previous phase (day 49 of
protocol II) and will last 4 weeks i.e. the time comprised between the first and the second
administration of protocol II. Imatinib administration will not be interrupted between the end of
protocol II and the beginning of interim maintenance.
6-MERCAPTOPURINE (6-MP): 50 mg/m
2
/day p.o., taken in the evening on the empty stomach
without milk (1 hour before or after dinner), days 1-28.
METHOTREXATE (MTX): 20 mg/m
2
/dose p.o. once a week days 8,15,22,29.
no MTX p.o on day 15 if IT MTX
IMATINIB : 300 mg /m
2
/day, days 1-29

In selected cases it could be necessary to start the two drugs with increasing doses according to the
patients compliance and/or haematological reconstitution.

CRANIAL IRRADIATION during interim maintenance:
For CNS prophylaxis :
Cranial irradiation will only be administered to patients older than 4 years at the dose of 12
Gy (single dose: 1.4-1.7 Gy)
For patients younger than 4 years, 8 additional intrathecal injections will be performed :
o on days 1 and 15 of interim maintenance
o on days 1 and 38 of second administration of protocol II
o and 4 in the continuation therapy

For Patients with CNS-disease:
Patients older than 2 years will receive 18 Gy (single dose: 1.4-1.7 Gy).
Patients younger than 2 years will not receive any irradiation but 10 additional intrathecal
injections
o on days 1 and 15 of interim maintenance
o on days 1, 18, 38 and 45 of second administration of protocol II
o and 4 in the continuation therapy


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5.8 Second administration of Protocol II
It will start immediately after the interim maintenance provided the patient is in good general
condition and adequate ANC ( 500/l) and platelet counts ( 50.000/l) are documented.


Figure 9.

5.8.1 Phase IIa

DEXAMETHASONE (DXM) : 10 mg/m
2
/day p.o. in 3 doses, day 1-21, then tapered over 10 days
by reducing the dose by 50% q 3 days.

VINCRISTINE (VCR): 1.5 mg/m
2
/dose i.v. (maximum dose 2.0 mg/dose), day 8, 15, 22, 29.

DOXORUBICIN (DOX)/ADRIAMYCIN (ADR): 25 mg/m
2
/dose i.v. to be infused over 1 h on
days 8, 15, 22, 29.

L-ASPARAGINASE (L-ASP) E. coli (medac or kidrolase): 10.000 IU/m
2
/dose, over 1 h i.v. In
case of an allergic reaction, PEG-ASP(ONCASPAR) may be used in a single dose of 1000 I.E./m
2
over 1 h i.v.

IMATINIB : 300 mg/m2/day orally, days 1-35 (total 35 days)
Day 1 8 15 22 29 36 43 50
DEXA p.o./i.v. 10 mg/m
2
/d
VCR i.v. 1.5 mg/m
2
CPM p.i. (1 h) 1000 mg/m
2

DOX p.i. (1 h) 25 mg/m
2

L-ASP
(E.coli)
p.i. (1 h) 10,000 U/m
2

ARA-C i.v. 75 mg/m
2
/d
57 63
IMATINIB p.o. 300 mg/m
2
/d (d 1-63)
6-TG p.o. (14 d) 60 mg/m
2
/d
B
M
/
M
R
D

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INTRATHECAL METHOTREXATE only if NO IRRADIATION in interim maintenance :
day 1 (and day 18 if CNS disease), age-dosed:
AGE MTX
1 year <2 years 8 mg
2 years <3 years 10 mg
3 years <4 years 12 mg

5.8.2 Phase IIb

It starts on day 36 of protocol II provided the patient is in good general condition and adequate
ANC ( 500/l) platelet counts ( 50.000/l) are documented.

CYCLOPHOSPHAMIDE (CPM): 1000 mg/m
2
/dose i.v. (1 hour) days 36.
Associate: * hyperhydration 3.000 ml/m
2
over 24 hours : Gluc. 5%+ NaCl 0.45%+ 90 mEq/m
2

KCl.
* MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start).
* FUROSEMIDE 0.5-1 mg/kg i.v if input>output +400 ml/m
2
/12h.
Please consider adequate anti-emetic supportive therapy.

6-THIOGUANINE (6-TG): 60 mg/m
2
/day p.o., taken in the evening on the empty stomach without
milk (1 hour before or after dinner), days 36-49 (total 14 days).

CYTOSINE ARABINOSIDE (ARA-C): 75 mg/m
2
/day s.c. o i.v. in one daily dose, days 38-41,
45-48.
Each 4-day cycle should be started when WBC>500/l and platelets >30.000/l; each cycle when
started should not be stopped unless for acute infection (please consider that fever might be also
induced by the drug.

IMATINIB : 300 mg/m
2
/day orally, days 36-63 (total 28 days) for all patients.

INTRATHECAL METHOTREXATE only if NO IRRADIATION in interim maintenance:
days 38 (and day 45 if CNS disease) (together with ARA-C cycles),dosage according to age:
AGE MTX
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1 year <2 years 8 mg
2 years <3 years 10 mg
3 years <4 years 12 mg

5.9 Continuation therapy
Continuation therapy will start 2 weeks after completion of delayed intensification and is
based on antimetabolite drugs. Imatinib administration will not be interrupted between the end of
phase IB and the beginning of continuation therapy.

6-MERCAPTOPURINE (6-MP): 50 mg/m
2
/day p.o., taken in the evening on the empty stomach
without milk (1 hour before or after dinner).

METHOTREXATE (MTX): 20mg/m
2
/weekly p.o.
no MTX p.o the day of IT MTX/ARAC/PRED

IMATINIB : 300 mg/m
2
/day p.o.

INTRATHECAL THERAPY only if NO IRRADIATION in interim maintenance: one
intrathecal injection each 3 months with the first one on day 15 for a total of 4 in the continuation
therapy
dosage according to age:
AGE MTX ARA-C PRED
1 year <2 years 8 mg 20 mg 6 mg
2 years <3 years 10 mg 26 mg 8 mg
3 years <4 years 12 mg 30 mg 10 mg

Chemotherapy will be modulated to keep WBC count between 1,000 and 3,000/l. The dosage of
the two drugs will be adjusted accordingly:

Leukocyte count / l Dose of 6-MP/MTX

<1.000 0%
1.000-2000 50%
2000-3000 100%
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>3.000 consider to increase the dosage to achieve a
WBC count between 2000 and 3000/l

ANC < 500/l 0%
Lymphocytes<300/l 50%


COMPLETION OF TREATMENT

Total duration of chemotherapy will not exceed 24 months. At the time of treatment completion
confirm CR by bone marrow aspirate and CSF examination.

6.0 Investigational drug


Glivec (IMATINIB) will be supplied by Novartis as 100 mg capsules packaged in
polyethylene bottles. Medication labels will comply with the legal requirements of each country and
will be printed in the local language. They will supply no information about the patient, just the
patient identification number. The storage conditions for the study drug will be described on the
medication label. Bottles must be stored in a safe, secure location.
Glivec should be administered once or twice a day. Glivec is a local irritant and must be taken
in a sitting position with a large glass of water (250 ml/8oz; at least 100 ml/4 oz for children < 3
years of age).
If the child/patient can not swallow the capsules the drug should be administered according to the
following guidelines: pour the contents of a capsule by small portions into 20 ml of water, milk or
apple juice. Stir with a spoon and administer the suspension immediately afterwards. Do not use
any other beverage like Coca-Cola or orange juice. Note: the excipients used in the capsule will not
dissolve. However, they are white whilst the active substance is yellow. Thus if a white solid
residue remains in the glass, it does not matter as long as the capsule has been slowly added and
well dispersed to allow the active substance to dissolve during stirring. If a yellow residue is
observed, it means that the active substance was not completely dissolved and only a fraction of the
dose has been swallowed.
Medications, which interfere with P-450 cytochrom metabolism (see Appendix III), should be
avoided and recommended doses of acetaminophen, should not be exceeded. The following
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medications and foods can interfere with P-450 metabolism: grapefruit juice, erythromycin,
azithromycin, clarithromycin, rifampin and its analogs, fluconazole, ketoconazole, itraconazole,
cimetidine, cannabinoids (marijuana or dronabinol) and the leukotriene inhibitors used in asthma
such as zafirleukast and zileuton. In addition, drug interactions in patients receiving
prochlorperazine (Compazine) and coumadin are possible. Patients who require
prochlorperazine during therapy should be monitored for extrapyramidal symptons and
those on coumadin should have weekly prothrombin times while on therapy. These
medications should not be used during IMATINIB administration unless there is unavoidable
medical need and no other appropriate alternative agents are available. Also, acetaminophen
should not be taken in greater than the recommended dose.


7.0 Stem cell transplantation: All patients will be screened for an HLA-identical family or
unrelated donor.
Good-risk patients: patients with a genotype-matched donor (9/10 or 10/10), will receive HSCT,
while the others will continue on chemotherapy, thus receiving IMATINIB in combination with the
standard chemotherapy.
Poor-risk patients: patients will be eligible for any type of donors (matched or mismatched family
donors, unrelated or haploidentical donors). Patients not transplanted will continue on
chemotherapy, thus receiving IMATINIB in combination with the standard chemotherapy.

7.1 Use of Imatinib after stem cell transplantation:
The use of IMATINIB is recommended in all HSCT recipient.
An initial dose of 200 mg/m
2
daily will be administered to all HSCT recipient provided they have a
satisfactory PTL and WBC count with stable neutrophils engraftment (PTL > 50 x 10
9
/L; WBC >
1.5 x 10
9
/L; neutrophils > 0.5 x 10
9
/L for at least 15 days).
Imatinib dosage can be increased to a maximum of 300 mg/m
2
daily if well tolerated by the patient.
Imatinib administration is suggested throughout the first year post-transplantation, till day +365
from HSCT.
It is recommended that a bone marrow aspirate with morphologic evaluation and PCR detection of
BCR/ABL is done before the beginning of post-transplant Imatinib and every 3 months for the first
year post-transplantation.
During Imatinib post-transplant administration weekly assessment of hepatic function and
complete blood count is required.
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8.0 Therapy modifications for toxicity (all phases)
8.1 Treatment toxicity during chemotherapy of Phase 1B, consolidation and re-induction by
using protocol II
Based on the closed treatment protocol AIEOP and BFM-ALL 95, patients enrolled in high-
risk schedule, require careful monitoring to prevent fatal or life-threatening complications. On
average, these patients spent approximately 100 days in the hospital during the five intensive
treatment phases covering the first nine months from diagnosis (27). However, the death rate in first
CR was only 2%, justifying wider application of this therapy in patients with high-risk ALL.
Although this treatment regimen included a high cumulative dose of anthracyclines (daunomycin
and doxorubicin) of 410 mg/m
2
, the cardiac function was not reported as a clinical problem after
treatment completion in this study. Some relevant parameters related with the treatment burden are
summarized in the following table.
Prot. Ia Prot.
Ib
Consoli-
dation
blocks**
Prot. II
(1
st
)
Prot. II
(2
nd
)

Number of patients analysed 182 157 124 109 31

Red blood cells
Patients receiving 1 unit (%) 85 96 90 69 65
No. of units (mean*) 2.9 3.1 3.7 2.4 2.1

Platelets
Patients receiving 1 unit (%) 51 36 70 16 23
No. of units (mean*) 4.3 3.6 5.1 3.6 3.4

IV antibiotic therapy
Patients (%). 46 37 82 46 74
Duration in days (mean*) 11 7 14 9 14

Central venous line ***
Patients (%) 67 75 83 80 74
No. days (mean*) 35 50 68 74 78

Hospitalization
Patients (%) 97 85 99 85 87
No. days (mean*) 22 14 32 11 19

Phase duration (days)
Scheduled by protocol 42 42 63 64 64
Observed (mean*) 46 59 73 81 89

* Mean values estimated including only patients who actually required the specific support.
** Data presented pertain to the entire phase (3 blocks)
*** Central line data are cumulative

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8.2 Therapy modifications for IMATINIB toxicity
Non-Hematologic Toxicity
Grade 3/4
If a patient experiences unexpected non hematological Grade 3-4 toxicity, study drug must be
withheld until the toxicity has resolved to < Grade 2 or lower. An assessment of possible drug
interactions should be performed, and any drug that is suspected as contributing to the toxicity
should be reevaluated regarding its dosage and/or necessity of administration. When toxicity is
grade 2 or lower, IMATINIB should be reintroduced at 20% less dose.

Hepatic Toxicity:
Patients with a total serum bilirubin < 1.5 x ULN at baseline who experience Grade 3-4 elevations
should be managed using the criteria detailed above for non-hematological toxicity

Hematologic Toxicity
Patients developing anemia are transfused at the discretion of the investigator. No dose reductions
are foreseen for any grade of anemia, except for Grade 3 and 4 anemia resulting from an acute
cause considered to be related to administration of IMATINIB (e.g. severe gastrointestinal
hemorrhage).
In the event of Grade 3 thrombocytopenia (platelets 10.000-<50.000/l) or neutropenia (500<1000
/l) not accompanied by clinical manifestations, i.e. significant bleeding or neutropenic fever,
potential causes of the cytopenias should be considered (e.g, leukemic progression, infection); if the
thrombocytopenia or neutropenia are attributed to the study drug, the dose will be reduced at 20%
less dose.
With the occurrence of Grade 4 thrombocytopenia (platelets <10.000/l) ,not accompanied by
clinical manifestations, platelets support and continuation of the drug are suggested.
G-CSF is permitted in the case of neutropenic fever or suspected drug induced neutropenia. If
Grade 3 or 4 thrombocytopenia or neutropenia are accompanied by clinically significant bleeding or
evidence of an infection, IMATINIB will be interrupted until toxicity has resolved to grade 2 or
lower and the clinical situation has stabilized; IMATINIB will then be restarted at 240 mg/m
2
daily.

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9.0 Visit schedule and assessments
Visit schedule
Patients must be followed at the study centers according to the visit schedule and assessments
according to national study-group policy. Provided there are no safety concerns, patients may be
evaluated by the referring physician after the first month of treatment. The referring physician must
agree to perform all required evaluations as requested by the protocol for those specific visits, and
agree to forward copies to the study center regularly. Patients must be evaluated at the study centers
for all bone marrow assessments.
Efficacy assessments
Assessment of efficacy during the first 6 months of treatment is based on bone marrow cytology
(histology only in case of a dry aspirate) and molecular evaluation of MRD according to the time
points in Fig 3 (at the beginning of Phase IB, of each blocks and before the reinduction). Analysis
of residual disease by flow cytometry is optional.
Minimal residual disease
MRD will be assessed by quantitative real-time PCR of mononuclear bone marrow and peripheral
blood cells collected at specified time points (see Fig 3). To guarantee comparability of data, it is
essential that the analyses are performed in central laboratories (one for each country) that agree on
standard procedures. MRD evaluation will be performed by quantitative PCR amplification of the
BCR-ABL fusion gene, according to the Guidelines of the European Against Cancer Project on
STANDARDIZATION AND QUALITY CONTROL STUDIES OF REAL TIME RT-PCR FOR MINIMAL RESIDUAL
DISEASE DETECTION OF FUSION GENE TRANSCRIPTS IN LEUKEMIA - A EUROPE AGAINST CANCER
PROGRAM (28). Comparative data will be obtained by using Ig and TcR gene amplification as
previously reported (29).

Cytogenetic and FISH analysis
It is recommended that a cytogenetic and FISH analysis will be performed on bone marrow samples
obtained prior to start of IMATINIB and in the event of relapse or disease progression as
determined by substantially increasing MRD levels. A minimum of 20 metaphases should be
examined whenever possible.
Hematological remission
For the purpose of this study, a hematological response includes any of the following:
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1) complete hematological remission,
2) no evidence of leukemia in peripheral blood and bone marrow, without full peripheral blood
recovery,
Each of these response categories is described in detail below. Hematological response must be
confirmed after > 4 weeks.
1) Complete hematological remission requires that all of the following are present:
a) Adequate bone marrow cellularity with a blast count < 5%
b) No peripheral blood blasts
c) ANC 1500/l
d) Platelet count 100.000/l
e) No evidence of extramedullary involvement
2) No evidence of leukemia in peripheral blood and bone marrow, without full peripheral blood
recovery requires that the following are present:
a) Blast count < 5% in bone marrow
b) No peripheral blood blasts
c) Platelet count > 20.000/l platelet transfusion independent and no evidence of bleeding)
d) No evidence of extramedullary involvement

For the purpose of assessing hematological response, peripheral blood samples and bone marrow
aspirates will be performed, and extramedullary leukemic involvement will be assessed by physical
examination.

Resistance to treatment (only for Poor-risk group)

5% of blasts in the bone marrow aspirate after the three blocks of consolidation in patients who
enter the poor-risk group because of no-CR at the end of induction

Safety assessments
Safety assessments will consist of monitoring and recording all toxicity and serious adverse events.
Hematology, liver function tests (SGOT [AST], SGPT [ALT], LDH, alkaline phosphatase and
bilirubin) and other biochemistries (BUN [urea], creatinine and uric acid) will be monitored weekly
during the time of concomitant IMATINIB administration. Thereafter, hematology and liver
function tests will be monitored according to national study protocols.
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Toxicity
Information about all toxic events, whether volunteered by the patient, discovered by the
responsible investigator, or detected through physical examination, laboratory test, or other means,
will be collected and recorded on the Toxicity Form. An adverse event is any undesirable sign,
symptom or medical condition occurring after starting treatment , in any arm.
As far as possible, each toxic event will be reported by the NCI/NIH Common Toxicity Criteria
severity grades 1 4.
Serious adverse events (SAE)
Each Serious Adverse Event (SAE) must be reported by the clinical center to the clinician
responsible (contact person) of its own national study group, within 24 hours of learning of its
occurrence, even if is not felt to be treatment-related. After ensuring that the forms be accurately
and fully completed, the clinician who is the group contact person must send the SAE form
immediately to the local Novartis representative and to the Coordination Unit. Follow-up
information about a previously reported SAE must also be reported within 24 hours with the same
modalities.
Information about all serious adverse events will be collected and recorded on the SAE Form,
according to Novartis standard.
A Serious Adverse Event is an undesirable sign, symptom or medical condition which:
1. is fatal or life-threatening
2. required or prolonged hospitalization
3. results in persistent or significant disability/incapacity
4. constitutes a congenital anomaly or a birth defect
5. are medically significant, may jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed above.
Events not considered to be SAE are hospitalizations occurring under the following circumstances:
planned before entry into the clinical study
for elective treatment of a pre-existing condition
occur on an emergency, outpatient basis and do not result in overnight hospitalization (unless
fulfilling the criteria above)
routine treatment or monitoring of the study indication and not associated with any deterioration
in condition.
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For instructions about returning Serious Adverse Event Report Forms to the study secretariat refer
to Novartis standards, see Appendix V.
Laboratory evaluations
Hematology
Peripheral blood will be drawn weekly during the time of concomitant IMATINIB administration.
Thereafter, hematology and liver function tests will be monitored according to national study
protocols. Hematology includes assessment of hemoglobin, total WBC count, ANC, platelet count,
and a differential count including neutrophils, bands, lymphocytes, monocytes, eosinophils,
basophils, early forms, and blast percentage.
The ANC used by the center to make dose adjustments is to be recorded on the CRF. For analysis
purposes however, the ANC will be calculated automatically from WBC x the total segmented
neutrophils plus bands x 10
9
/L.
Biochemistry
Liver function tests - SGOT (AST), SGPT (ALT), LDH, alkaline phosphatase and bilirubin - will be
performed weekly during the time on concomitant IMATINIB administration. During
chemotherapy alone, biochemistries will follow the national study treatment policy.
Physical examination
A physical examination, including vital signs, will be performed during screening. The physical
examination will be repeated monthly throughout the study, including assessment of vital signs.
Information about the physical examination and vital signs must be present in the source
documentation at the study site. Clinically significant findings present prior to the start of study
drug must be included in the Relevant Medical History/Current Medical Conditions CRF. Clinically
significant findings made after the start of study drug which meet the definition of an adverse event
must be recorded on the Adverse Event Case Report Form
Performance Status
Performance status will be measured at baseline using the Lansky Performance Status Score.
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10 Statistical considerations

10.1 Randomization

The randomized part of the study was stopped based on external evidence (COG
AALL0031) and on DSMC consensus. Thus this present part of the protocol must be
neglected.
Each child who is alive and in CR after induction in the Good-Risk group is eligible for randomization.
The request for randomization should be made, after consent from parents or guardians is obtained,
when the patient is known to be Ph+ and the parameter of the early response (Prednisone response or
BM at day 15, 21) is known. This will allow a timely start of phase Ib. There might be very few cases,
randomized in the Good-Risk group thanks to the achievement of an early response, who are not in CR
at the end of induction. In these cases there will be a shift to the Poor-Risk group treatment, whatever
the assigned arm. Randomization will be performed by the data center of each group, so that treatment
arms will be balanced within each group. Patients will be randomized by telephoning to the data center
which will perform a check on the eligibility criteria before assignment. Therefore, at the time of
randomization, at least the registration, diagnosis and induction/response data should be available at the
data center in order to verify eligibility. The random assignment will be produced by an automatic
procedure based on random permuted blocks.
If parents do not give consent , the center should not ask for randomization and the treatment arm
should be decided case by case.


10.2 Analysis

The primary analysis will be the evaluation of the outcome for all Ph+ALL patients in terms of
EFS by considering the time from beginning of phase Ib to the following endpoints: resistance,
relapse, death in CCR, second malignancy. The evaluation of outcome will also be performed in
terms of survival time from beginning of phase Ib (endpoint is death from any cause).

Secondary analyses will include:
1. Evaluation of EFS within each risk group
2. The evaluation of MRD as molecular indicator of disease burden at the end of consolidation
(i.e. end of blocks, time point 5, TP5) in all patients: the proportion of patients with negative
MRD levels and alive in CCR at TP5 will be the measure of response.
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3. The description and analysis of the MRD pattern (slope) based on 5 measurements taken at
subsequent time points from the start of phase IB to the beginning of the re-induction phase.
4. The evaluation of the role of the molecular indicator as surrogate for DFS.
An analysis censoring HSCT will also be performed.

10.3 Sample size

This study asks the question whether the continuous exposure to IMATINIB, on top of a BFM
oriented protocol affects the prognosis of children with Ph+ALL. As Ph+ALL is estimated to account
for 2.5% of the childhood ALL population, the participating groups will have the following expected
recruitment per year:

AIEOP (Italy) 8
BFM (Germany, Switzerland, Austria) 11
COALL (Germany) 3
CPH (Czech Republic) 1
DCOG (the Netherlands) 3
EORTC-CLCG (France, Belgium) 6
FRALLE (France) 4
NOPHO (Scandinavian countries) 4
UKCCSG (United Kingdom) 9
HONG KONG 2
PINDA (Chile) 4
Total: 55 Ph+ALL cases per year

With a 2 year recruitment and accounting for approximately 15% of patients who do not enter this
protocol for lack of consensus, clinical considerations or logistical reasons, a total of 90 patients are
expected to be enrolled and evaluable. In keeping with data from COG AALL0031 study, these
patients are expected to have better EFS than patients treated with imatinib according to the original
EsPhALL protocol. With 90 patients recruited, the study will have 90% power to show an
advantage of 20% EFS over the historical EsPhALL figure of 60% 3-year EFS and 80% power to
show a 17% advantage ( =0.05, logrank test). A 20% advantage would correspond to the 80.5% 3-
year EFS figure reported by COG ALL0031 on cohort 5.

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10.4 Interim analysis
The randomized part of the study was stopped based on external evidence (COG )
and on DSMC consensus. Thus this present part of the protocol must be neglected.

Interim analysis evaluates, while the trial is still in progress, the randomized question on treatment
effect. The aim is to avoid prolongation of the study beyond a time when clear superiority can be
demonstrated for one of the randomized treatment schedules. One intermediate analysis is planned to
be performed after the first two years of randomization on the primary end-point. The significance level
of the interim test, adjusted for the multiplicity of looks according to OBrien and Fleming (31), is
calculated with a total type I error =0.05 and a power of 80% (two-tailed test) and is shown below:

Significance levels for interim analysis

Years First Final
p-level 0.003051 0.05
Patients 70 140
Years from 1st
randomization
2 4



10.5 Secondary analysis on response
The randomized part of the study was stopped based on external evidence (COG )
and on DSMC consensus. Thus this present part of the protocol must be neglected.

Specifically, for the evaluation of response in term of MRD, past experience suggests that a reasonable
estimate of the proportion of MRD negative patients, at the end of consolidation, i.e. after blocks
(identified in the figure below as TP3), is about 40% as shown by the following data derived from a
prospective study on MRD in Ph+ ALL patients (30).

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This experience is based on a qualitative, end-stage PCR evaluation of MRD, whereas the protocol will
analyze MRD by quantitative-PCR. A negative result for MRD (identified by the green dot) was
referred to a nested-PCR approach with a sensitivity of at least 10
-4
(30).
For sample size calculation and analysis based on the secondary end-point, i.e. the negativity of MRD
at TP5, either one of the following events would be considered as treatment failure, i.e. non negativity
at TP5:
Positive MRD at TP5
Death in CR within TP5
Relapse within TP5.
In the available data used above, none of the 18 patients who were good responders to PDN and in CR
at the end of induction Ia, either relapsed or died during consolidation.
We considered a baseline value for response of 35% in order to take into account and additional 5%
possibility of occurrence of death in CR or relapse before TP5. Different hypotheses on possible
differences in the proportions of MRD negative patients between the two arms were also considered.
The table reports the power calculations under each scenario for the final two-sided test on the
difference in MRD negative proportions (null hypothesis: no difference) assuming the first type error
=0.05.



6-MP + MTX+PDN/VCR Ia
Rx
HR
B
1
B
2
B
3 G-CSF II
Interim
Maint .
IT- MTX
1
4
d
4
2
d
3
m
5
m
2
4
m
9
m
II
TIT
Ib G-CSF G-CSF
1
2
m
d
d
d
Status
d
-
d
d
4
8
m
3
6
m
4
2
m
3
0
m
d
d
b
d
d
TP1 TP2 TP3
1
3
9
10
12
14
22
24
26
5
17
2
4
11
13
15
16
21
23
25
27
6
18
G
G
G
G
G
G
7
G
G
G
G
G
G
G
G
G
G
G
P
P
P
P
P
P
P
A
B
C
D
R
d 20 G
R
R
R
R
RT-PCR negative
RT-PCR positive
HSCT
Relapse
CCR
Non-CCR
Observation time
b 19 G
R
8
G
TP4
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Sample size: 140 subjects
35% baseline proportion of MRD negative patients

Proportion of MRD
negative patients in
experimental group
Absolute difference in
proportions as
compared to baseline
Power
50% 15% 37
55% 20% 60
60% 25% 80


The power calculations show that, with a 4-year recruitment, in the presence of a marked difference in
the proportion of MRD negative patients between the two treatment arms, i.e. 25% absolute difference
or more, the study could have sufficient power (80%).
This sample size calculation could be reviewed in the light of the accumulating quantitative data on
MRD by considering the comparison of the mean levels of MRD in the two groups at TP5.

10.6 Methods of analysis
The EFS in the overall group of Ph+ patients and in the two risk groups will be calculated using the
Kaplan-Meier estimator and the 3 year figure with 95% CI reported (based on Greenwood
variance). For historical comparison with the original EsPhALL protocol, a Cox model will be fitted
to the data, adjusting for sex, age at diagnosis, WBC count at diagnosis and treatment (HSCT would
be censored or, in alternative, included as a time-dependent variable), after check of the model
adequacy, in order to compare the two study cohorts.
As for the secondary objectives of the study on response, the proportions of MRD negative patients
in CCR at TP5 will be evaluated and compared between poor and good risk patients.
Also, the different longitudinal profiles in MRD response up to TP5 will be evaluated, if possible,
in order to study their impact on prognosis, i.e. on the clinical end point (EFS).
The same methods of analysis will be adopted for the set of Poor Risk patients (observational
study).

10.7 Early stopping guidelines for treatment related mortality

These guidelines are necessary given the new strategy of the protocol, which introduces IMATINIB
into the standard BFM-like chemotherapy for the treatment of childhood leukemia. They are
designed to ensure that the treatment would be stopped as early as possible if its application is
associated with a treatment related mortality higher than acceptable in standard treatments.
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The table below shows the minimum number of treatment related deaths (excluding deaths after
HSCT) at which experimenters and DMC should carefully evaluate the possibility of stopping the
application of the treatment.
Guidelines for early stopping due to treatment related mortality

No. of events
No. of subjects in
study arm
2 11-15
3 16-25
4 26-35
5 36-45
6 46-56
7 57-67
8 68-78

The method applied for developing these guidelines follows a Bayesian approach (32), extending
that of Metha and Caine (33). In these guidelines, the maximum acceptable level of p1=7%
probability of treatment related deaths was considered. The number of failures is assumed to be
taken from a Binomial distribution. The prior distribution for the probability of the endpoint of
interest was taken as a Beta (1,1), corresponding to an uninformative Uniform distribution. The
stopping bounds reported in the table are the experimental results that give a posterior probability of
90% or more, of observing p17%.


11.0 Organizational aspects and data management

Each participating group will refer to the contact person of the group and to its own usual network
of clinical centers, data center and experts (statistician, laboratories, etc) for:
The implementation of this protocol
The monitoring of the groups data and of the quality of the data
Pag.2-4 report names and addresses of contact persons of each participating group. The
international study coordinators, and the trial data center will act as a co-ordination unit for the
exchange of information among groups and for the evaluation of their data.

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11.1 Data Collection

The trial data center designed a specific web-based system for data collection which is used by each
participating centre.
The participants have agreed upon:
registration of each new child or adolescent newly diagnosed with Ph+ ALL;
collection by web of a selected set of data on each patient who enters the protocol;


The set of data to be collected and evaluated by the participants are listed in Appendix IV. Each
group will:
use the same form for data collection that include the data items listed in Appendix IV;
centralize the forms for input and quality checks in its own data center, according to the
approach routinely used in the group;
input of the data in the same WEB database provided by the trial operation centre;
provide yearly the data file to the coordination unit.

The major requirements that each group will have to ask to the clinical center are:
1. to register at the group data center each new patient diagnosed with Ph+ ALL, regardless of
whether he/she will subsequently enter the present protocol. This is necessary in order to know
which percentage of eligible patients is treated according to the protocol. Registration should be
done as soon as the presence of t(9;22)(q34;q11) in newly diagnosed childhood ALL has been
be documented;
2. to report immediately (within 24 hours recognition) by fax specific events ( death,relevant
toxicity) to the responsible clinician of each group, to the local Novartis and to the coordination
unit, with the appropriate WEB forms. This is strictly necessary for the international standards
in phase II studies on IMATINIB;
3. to send to the group data center on a regular basis the forms with information on diagnosis,
response, randomization, treatment, and toxicity as soon as they can be completed.
4. to up-date follow-up at the end of each calendar year.

For eligible patients registered but not included in the present protocol, follow-up data only will be
routinely requested.

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11.2 Data evaluation and analysis (34)

The trial data center, in collaboration with the study chairman and the contact persons and the
statisticians of each group, will be responsible to pool and evaluate the data reported in the WEB
system according to the protocol aims.
The data evaluation will be done with the following steps:
Follow up will be updated at December of each year
The data will be used for the trial aims only;
A report will be produced each year on the study progress (recruitment, toxicity and so on) and
the interim analysis performed when planned;
Reports will be circulated via WEB by the coordination unit to the contact persons of the groups
and to the Data Monitoring Committee (DMC);
Members of the DMC are experienced researchers (one clinician and one statistician) not
involved in the trial who will be responsible of providing the investigators with guidance on the
trial conduction and, in case of problems, on whether the trial should be stopped, modified or
continued.

The trial database will be used for the trial aims only, under the responsability of the
participating groups. Novartis will be informed of the SAE and eventually of trial results.

11.3 Ethics and Good Clinical Practice

The last revision of the Helsinki Declaration as well as the previsions of the Oviedo Declaration,
provide the general framework for the ethical conduct of the study.
The study protocol is designed to ensure adherence to Good Clinical Practice (GCP) principles and
procedures.

11.4 Informed consent
Informed consent forms have to be written by each group itself, adapted to the local situation.




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12. Definitions

Absolute Neutrophil Count (ANC)
The ANC is defined as the WBC/L times the neutrophil percentage

Absolute Blast Count
The absolute blast count is defined as the WBC/L times the blast percentage
Central Nervous System (CNS ) Disease at Diagnosis
CNS leukemia is defined as an elevated CSF WBC ( 5 cells/L) and a cytocentrifuge preparation
demonstrating lymphoblast cells. CNS leukemia may also be diagnosed when the CSF WBC is
normal, but clinical signs of CNS leukemia such as facial nerve palsy or hypothalamic syndrome
are present. Patients who have less then 5 cell/L and a positive cytospin will not be considered to
be CNS positive.

Overt Testicular Leukemia at Diagnosis
Unilateral or bilateral testiculomegaly with leukemic infiltration confirmed by biopsy. Equivocal
findings on testicular exam warrant biopsy

Bone Marrow Status
M1: < 5% blasts of all nucleated cells including erythropoiesis. In case of regenerating marrow
with a high erythropoietic predominance, at least a total count of 100 non-erythropoietic cells
should be counted.
M2 : 5-25% blast all nucleated cells including erythropoiesis. In case of regenerating marrow with
a high erythropoietic predominance, at least a total count of 100 non-erythropoietic cells should be
counted.
M3: > 25% blasts in a bone marrow aspirate.

Resistance to Induction
5% of blasts in the bone marrow aspirate.

Resistance to protocol IB
5% of blasts in the bone marrow aspirate at the end of protocol IB ( day 78) in patients resistant to
Induction.
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Resistance to treatment
5% of blasts in the bone marrow aspirate after the first three blocks of consolidation in patients
not resistant to protocol IB.

Late response
<5% of blasts in the bone marrow after the phase IB or after the three blocks of consolidation.
Complete remission

< 5% blasts in the bone marrow aspirate regardless of the proportion of mature lymphocytes at the
end of theInduction.

Continuos complete remission
Persistence of CR status.

Bone marrow relapse
25% blasts in the bone marrow aspirate after that of 1
st
CR has been achieved.


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13. References
Therapy and Diagnosis of ALL
1. Pui C-H, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998; 339:605-615.
2. Schrappe M and Pui C-H. Leukemia. 2000;14: 2193-2320.
Ph+ALL in children
3. Aric M,Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia
chromosome-positive acute lymphoblastic leukemia. N Engl J Med. 2000;342:998-1006.

4. Schrappe M, Aric M, Harbott J, et al. Philadelphia chromosome-positive (Ph+) childhood acute
lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable
treatment outcome. Blood. 1998; 92:2730-2741.

5. Ribeiro RC, Broniscer A, Rivera GK, et al. Philadelphia chromosome-positive acute
lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial
white blood cell counts. Leukemia. 1997;11:1493-1496.
Stem cell transplantation
6. Uderzo C, Valsecchi MG, Balduzzi A et al. Allogenic bone marrow transplantation versus
chemotherapy in high-risk childhood acute lymphoblastic leukemia in first remission. Br J
Haematol. 1997; 96:387-394.
7. Marks DI, Bird JM, Cornish JM, et al. Unrelated donor bone marrow transplantation for children
and adolescents with Philadelphia-positive acute lymphoblastic leukemia. J Clin Oncol.
1998;16:931-936.

8. Goldstone AH, Prentice HG, Durrant J, et al. Allogeneic transplant (related or unrelated donor) is
the preferred treatment for adult Philadelphia chromosome positive (Ph+) acute lymphoblastic
leukemia (ALL). Results from the international ALL trial (MRC UKALLXII/ECOG E2993).
Blood. 2001;98:856a.

9. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia
chromosome-positive acute lymphoblastic leukemiaresults of the prospective multicenter LALA-
94 trial. Blood. 2002;100:2357-2366.

10. Marks DI, Aversa F, Lazarus HM. Alternative donor transplants for adult acute lymphoblastic
leukaemia: a comparison of the three major options. Bone Marrow Transplant. 2006;38:467-475.

11. Wassmann B, Pfeifer H, Stadler M, et al. Early molecular response to posttransplantation
imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+
ALL). Blood. 2005;106:458-463.

12. Anderlini P, Sheth S, Hicks K, Ippoliti C, Giralt S, Champlin RE. Re: imatinib mesylate
administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant.
2004;10:883-884.

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13. Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic administration of imatinib after
hematopoietic cell transplantation for high-risk Philadelphia chromosomepositive leukemia.
Blood. 2007;109:2791-2793.



BCR-ABL and the ABL-Kinase Inhibitor IMATINIB
15. Sausville EA. A Bcr/Abl kinase antagonist for chronic myelogenous leukemia: a promising path
for progress emerges. J Natl Cancer Inst. 1999; 91: 102-103.

16. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell.
2002;1:31- 36.

17. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine
kinase on the growth of Bcr-Abl positive cells. Nature Med. 1996; 2: 561-566.
18. Deininger MW, Goldman JM, Lydon N, and Melo JV. The tyrosine kinase inhibitor CGP
57148B selectively inhibits the growth of Bcr-Abl-positive cells. Blood. 1997; 90: 3691-3698.
19. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL
tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia
with the Philadelphia chromosome.N Engl J Med. 2001;344:1038-1042.

20. Sawyers CL, Hochhaus A, Feldman E, et al. IMATINIB induces hematologic and cytogenetic
responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase
II study. Blood. 2002;99: 3530-3539.

21. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to
IMATINIB mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652.

22. Cohen MH, Williams G, Johnson JR, et al. Approval summary for IMATINIB mesylate
capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935-942.

23. Ottmann OG, Druker B, Sawyers C, et al. Results of a phase II study to determine the safety
and anti-leukemic effects of IMATINIB in adult patients with advanced Philadelphia chromosome
+ve leukemias. Blood. Suppl. 1, 2000.
24.Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of IMATINIB in patients with
relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood.
2002;100:1965-1971.

25. Leis JF, Stepan DE, Curtin PT, et al. Central nervous system failure in patients with chronic
myelogenous leukaemia lymphoid blast crisis and Philadelphia chromosome positive acute
lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma. 2004;45:695-698.

26.Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural
mechanism for STI571 inihibition of Abelson tyrosine kinase. Science. 2000;289:4319-4327.
27. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosomepositive acute
lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407.

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28. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added to intensive combination
chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic
leukemia. Leukemia. 2005;19:1509-1516.

29. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome
by combination of imatinib and chemotherapy for newly diagnosed BCR-ABLpositive acute
lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol.
2006;24:460-466.

30. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of
imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic
leukemia (Ph+ ALL). Blood. 2006;108:1469-1477.

31. Fuster JL, Bermudez M, Galera A, et al. Imatinib mesylate in combination with chemotherapy
in four children with de novo and advanced stage Philadelphia chromosome-positive acute
lymphoblastic leukemia. Haematologica. 2007;92:17231724.

32. Burke MJ, Cao Q, Trotz B, et al. Allogeneic Hematopoietic Cell Transplantation (Allogeneic
HCT) for Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic
Leukemia (ALL). Pediatric Blood and Cancer. 2009; 53: 1289- 1294.

33. Schultz KR, Bowman WP, Aledo A, et al .Improved Early Event-Free Survival With Imatinib in
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group
Study. J Clin Oncol. 2009 Oct 5 (epub ahed of print).

34. Arico M, Valsecchi MG, Conter V, et al. Improved outcome in high-risk childhood acute
lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-
Muenster protocol II. Blood. 2002 ; 100:420-426.

35. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosomepositive acute
lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407

36. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome
by combination of imatinib and chemotherapy for newly diagnosed BCR-ABLpositive acute
lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol.
2006;24:460-466.

37. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of
imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic
leukemia (Ph+ ALL). Blood. 2006;108:1469-1477.

38. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with induction or
consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute
lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109:1408-1413.

39. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosomepositive acute
lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407.

40. Radich JP. Philadelphia chromosome-positive acute lymphocytic leukemia. Hematol Oncol Clin
North Am. 2001;15:21-36.

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41. Gandemer V, Auclerc M, Perel Y, et al. BMC Cancer. Impact of age, leukocyte count and day
21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia
chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE
93 study

Minimal residual disease
42.Gabert J , E. Beillard, V.H.J. van der Velden, et al. Standardization and quality control studies of
real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of fusion gene
transcripts for minimal residual disease detection in leukemia - A Europe Against Cancer Program.
Leukemia. 2003; 17: 2318-2357.
43.Van Dongen J.J.M., Seriu T., Panzer-Grmayer E.R., et al. Prognostic value of minimal residual
disease in acute lymphoblastic leukemia in childhood.Lancet. 1998; 352: 1731-1738.

44. Cazzaniga G, Lanciotti M, Rossi V, et al. A Prospective molecular monitoring of BCR/ABL
transcript in children with Ph+ ALL unravels differences in treatment response. Br J Haematol.
2002;119:445-453.
Statistics

45. OBrien, P.C. and Fleming, T.R. A multiple testing procedure for clinical trials. Biometrics.
1979; 35: 549-556.

46. Mariani, L. and Marubini, E. Design and analysis of phase II cancer trials: a review of statistical
methods and guidelines for medical researchers. International Statistical Review. 1996; 64: 61-88.

47. Metha, C.R. and Caine, K.C. Charts for the early stopping of pilot studies. J. Clin. Oncol. 1984;
2:676-682.

48. Valsecchi MG, Silvestri D, Covezzoli A, De Lorenzo P. Web-Based international studies in
limited populations of pediatric leucemia. Pediatric Blood and Cancer. 2008; 50:270-273.


















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Appendix I
Table for monitoring of MTX serum levels and intensification of LCV rescue

24 36 42 48 54 60 66 72 78 84 90 96
37,5 mg/mq
30 mg/mq
20 mg/mq
15 mg/mq
7,5 mg/mq
NO RESCUE
0
0,25
1
2
3
4
5
0
1
2
3
4
5
mol/L mol/L
CF CF
RESCUE STANDARD
RESCUE WITH CITROVORUM FACTOR (CF) AFTER HIGH
DOSE METHOTREXATE (HD-MTX)
5 gr/mq
Hours sincethe starting of HD-MTX
CF
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Appendix II
Notable laboratory value criteria, special methods and scales
Special scale
Lansky Performance Status Scale For Children

Score Performance
100 fully active, normal
90 minor restrictions in physically strenuous activity
80 active, but tires more quickly
70 both greater restriction of, and less time spent in, active play
60 up and around, but minimal active play, keeps busy with quieter
activities
50 gets dressed, but lies around much of the day, no active play, able to
participate in all quiet play and activities
40 mostly in bed; participates in quiet activities
30 in bed; needs assistance even for quiet play
20 often sleeping, play entirely limited to very passive activities
10 no play; does not get out of bed
0 unresponsive

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Appendix III: Drugs known to be metabolized by CYP450 isoenzymes

CYP450
isoenzyme
Substrates Inhibitors Inducers Markers
CYP2D6 Several
antidepressants
Neuroleptics
Beta-blockers
Antiarrhythmics
Codeine
Dextromethorphan
Ethylmorphine
Nicotine
Ajmaline
Chinoidine
Fluoxetine
Paroxetine
Quinidine
Ritonavir
None known Debrisoquine
Dextromethorph
an
CYP3A4 Acetaminophen
Carbamazepine
Cyclosporin
Digitoxin
Diazepam
Erythromycin
Felodipine
Fluoxetine
Nifedipine
Quinidine
Saquinavir
Steroids (e.g. cortisol)
Terfenadine
Triazolam
Verapamil
Warfarin
Clotrimazole
Ketoconazole
Ritonavir
Troleandomycin
Dexamethasone
Phenytoin
Rifampin
Troleandomycin
Dapsone
Erythromycin
Ketoconazole
Lidocaine

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Appendix IV Variables in the database

Study conduct is now organized via web, but with the same requirements listed
below.
In this WEB database all patients diagnosed with Ph+ ALL will be evaluated, regardless of
whether they entered the present protocol or not. For patients who do not enter the protocol
(registered only), possibly provide data on follow-up. For patients who enter the protocol,
please provide all data. Each group will provide the data according to the variables listed
below and the operation unit will produce, based on them, the database. The type of file
would be, in order of preference: SAS, Excel and ASCII. Dates are in the DDMMYYYY
format.


Diagnosis-treatment-follow-up file

Registration


Var Name Code Format

Identification number

UPN

use your own UPN


C

7
Initials (family, first name) INIT C 3

Group GROUP 1=AIEOP
2=BFM-Austria
3=BFM-Germany/Switzerland
4=ALL-REZ
5=COALL
6=DCLSG
7=EORTC
8=FRALLE
9=NOPHO
10=MRC
11= CPH
12=PINDA
13=HONG KONG
I 2
Date of birth DOB_ D 8

Sex SEX

1=Male
2=Female

I 1
Date of diagnosis DOD_ D 8

Enters the protocol ENTER 1=No
2=Yes

I 1
Reason for ENTER=No COENTER -1=Not applicable
Give your own code
I 2

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Diagnosis


Var Name Code Format

% blasts (peripheral blood) BLA -2=Not evaluable
-1=No data

I 3

WBC at diagnosis (/mmc) WBC -1=No data

I 7

Platelets (/mmc) PLT -1=No data

I 7

Hb (g/dl) HB -1=No data

R 4.1

FAB Morphology FAB 1=L1
2=L2
3=L1/2
4=L3
5=Not classified
9=No data

I 1

Peroxidase POX 1=Negative
2=Positive
3=Not done
9=No data

I 1

Immunophenotype IMMPHEN 1=Pro-T
2=Pre-T
3=Intermediate (cortical) T
4=Mature T
5=T-lineage not classified
6= Pro-B
7= Common
8=Pre-B
9=Mature B
10=B-lineage not classified
11=AUL
99=No data

I 2

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Var Name Code Format

Chromosomal abnormalities

Data on t(9;22)(q34;q11)



Karyotyping K_CA C

20
CNS involvement

CNS involvement CNS_INV 1=No
2=Yes
9=No data
I 1
Cells in CSF (/l) CSF_CELL -2=Not evaluable
-1=No data

I 3

Blast in CSF (%) BLA_CSF -2=Not evaluable
-1=No data

I 3

CSF contaminated with blood CSF_INV 1=No
2=Yes
3=No puncture
9=No data

I 1
Organ involvement
Hepatomegaly HEP_INV




1=No
2=Yes
3=Questionable
4=Not done
9=Not known

I 1
Cm below costal margin of
liver
MEA_LIV I 2.1

Splenomegaly SPL_INV 1=No
2=Yes
3=Questionable
4=Not done
9=Not known

I 1
Cm below costal margin of
spleen
MEA_SPL I 2.1

...



Other organ involvement OTH_INV

Please specify C 20


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Response to Prednisone/induction IA


Var Name Code Forma
t

Cumulative dose of Prednisone
(mg)
PDN_DOSE -1=Not known R 4.1

Blast cell count/l at day 8 COBLA_8 -2=Not evaluable
-1=No data

I 5

WBC/l at day 8 WBC_B -1=No data

I 7

BM day 15, % blasts BLA_15 -2=Not evaluable
-1=No data

I 3

BM day 21, % blasts BLA_21 -2=Not evaluable
-1=No data

I 3

BM day 33, % blasts BLA_33 -2=Not evaluable
-1=No data

I 3

Date of first complete remission DOCR1_

D 8
Risk group RG 1=Poor
2=Good
I
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Treatment


Var Name
Code Forma

Induction IA

Date of start Induction DOSI_ D 8

Date of end Induction (date of
last administration)
DOENDI_ D 8


Induction IB


...



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Transplantation


Var Name Code Forma
t

Considered eligible for
transplantation

ELHSCT 1=No
2=Yes
9=Not known

I 1
Search for unrelated donor DONOR 1=No
2=Yes
9=Not known

I 1
No. of siblings SIBL -1=No data

I 2
Hystocompatibility of siblings HYSTO 1=No
2=Yes
9=Not known

I 1
Date of HLA typing DOHLA_ D 8

Date of transplantation DOHSCT_ D 8

Phase of transplantation PHSCT 1=In 1
st
CR
2=Resistant disease

I 1
Type of transplantation THSCT 1=Autologous
2=Allogeneic (gen. HLA-id,
related)
3=Allogeneic (fen. HLA-id,
related)
4=Allogeneic (not HLA-id,
related)
5=Allogeneic (not specified)
6=Allogeneic (HLA-id,
unrelated)
7=Allogeneic (not HLA-id,
unrelated)
8=Syngeneic (identical twins)
9=No data

I 1

Source of transplantation SHSCT 1=BM
2=PBSC
3=Cord blood
Give your own code for other
types

I 1


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Follow-up


Var Name Code Forma
t

Date of first relapse DOREL_ D 8

Site of first relapse TOREL 1=BM
2=CNS
3=Testis
4=BM+CNS
5=BM+Testis
Give your own code for other
sites

I 2
Date of death DODEAD_ D 8

Cause of death CODEAD 1=Progressive ALL
2=HSCT related
3=2
nd
tumor
4=Sepsis
5=Pneumonia
6=Other infection
7=Haemorrhage
8=MOF
9=Other (specify in the note
space)
99=Not known

I 2
Phase of death PH_DEAD 1=Before start therapy
2=In induction, before CR
3=In first CR
4=After relapse
5=After 2
nd
neoplasm

I 1
Date of last follow-up DOLFU_ Equals date of death, if patient
died

D 8
Date of 2 malignant neoplasm DOSMN_ D 8

Type of 2 malignant neoplasm

T_SMN Give your own codes I 2
Note space

NOTE C 40




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Appendix V Serious Adverse Event Report
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